Glycolysis,Metabolic

Glycolysis is a metabolic pathway with sequence of ten reactions involving ten intermediate compounds that converts glucose to pyruvate. Glycolysis release free energy for forming high energy compound such as ATP and NADH. Glycolysis is consisted of two phases, which one of them is chemical priming phase and second phase is energy-yielding phase. As the starting compound of chemical priming phase, D-glucose can be obtained from galactose metabolism or imported by monosaccharide-sensing protein 1 from outside of cell. D-Glucose is catalyzed by probable hexokinase-like 2 protein to form glucose 6-phosphate which is powered by ATP.  Glucose 6-phosphate transformed to fructose 6-phosphate by glucose-6-phosphate isomerase, which the later compound will be converted to fructose 1,6-bisphosphate, which is the last reaction of chemical priming phase  by 6-phosphofructokinase with cofactor magnesium, and it is also powered by ATP. Before entering the second phase, aldolase catalyzing the hydrolysis of F1,6BP into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate can convert to each other bidirectionally by facilitation of triosephosphate isomerase. The second phase of glycolysis is yielding-energy phase that produce ATP and NADH. At the first step, D-glyceraldehyde 3-phosphate is catalyzed to glyceric acid 1,3-biphosphate by glyceraldehyde-3-phosphate dehydrogenase with NAD, which also generate NADH. ATP is generated through the reaction that convert glyceric acid 1,3-biphosphate to 3-phosphoglyceric acid. Phosphoglycerate mutase 2 catalyze 3-phosphoglyceric acid to 2-Phospho-D-glyceric acid,  and alpha-enolase with cofactor magnesium catalyzes 2-Phospho-D-glyceric acid to phosphoenolpyruvic acid. Eventually, plastidial pyruvate kinase 4 converts phosphoenolpyruvic acid to pyruvate with cofactor magnesium and potassium and ADP. Pyruvate will undergo pyruvate metabolism, tyrosine metabolism and pantothenate and CoA biosynthesis.


Sulfate/Sulfite Metabolism,Metabolic

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This pathway illustrates the conversion of sulfite to sulfate (via sulfate oxidase) and subsequent generation of adenylylsulfate (APS) via 3'-phosphoadenosine 5'-phosphosulfate synthase 2. APS is converted to phosphoadenylyl-sulfate (PAPS) via adenylylsulfate kinase. APS can also be regenerated from PAPS by 3'(2'), 5'-bisphosphate nucleotidase 1. PAPS is eventually converted to adenosine bisophosphate (PAP) through the action of several different enzymes including aryl sulfotransferase, chondroitin 4-sulfotransferase 13 and estrone sulfotransferase. The metabolism pathway in question is important for many reasons. Recall, that the sulfite ion is in fact the conjugate base of sulfurous acid. Moreover, this ion is found naturally in one of the worlds most popular beverages, wines. Beyond its natural occurence, sulfite ion had the property of stopping fermentation. As such, the addition of it to products such as wine can be used either as a preservative or to stop the fermentation process at a moment which is of interest. Finally, this preservation property goes beyond merely wines, and finds utility in dried fruits, potatoes, etc.


Galactose Metabolism,Metabolic

This pathway depicts the conversion of galactose into glucose, lactose, and other sugar intermediates that may be used for a range of metabolic process. Dietary sources of galactose are numerous, but some of the primary sources in the human diet can be found in milk and milk derivative products. This is because during digestion milk sugars and lactose are hydrolyzed into their molecular constituents (e.g. base monosaccharides). In milk, such monosaccharides include glucose and galactose. The metabolism of the sugar Galactose is occurs almost entirely in the liver, and its metabolism is the consequence of three steps or reactions. First, the phosphorylation of galactose is induced by a special enzyme with the predictable name, galactokinase, and produces galactose 1-phosphate. Second, this biproduct and a second molecule, UDP-glucose, undergo a reaction which leads to the formation of UDP-galactose and glucose 1-phosphate. Thus, this reaction produces 1 molecule of glucose 1-phosphate per molecule of galactose.This is mediated by the enzyme galactose-1-phosphate uridylyltransferase (GALT). The resulting UDP-galactose undergoes epimerization to form UDP-glucose via the enzyme UDP-galactose-4 epimerase (GALE). The UDP-glucose can be used in glucuronidation reactions and other pentose interconversions. In a reaction shared with other pathways, glucose 1-phosphate can be converted into glucose 6-phosphate. There are other pathways associated with galactose metabolism. For instance, galactose can be converted into UDP-glucose by the sequential activities of GALK, UDP-glucose pyrophosphorylase 2 (UGP2), and GALE. Galactose can also be reduced to galactitol by NADPH-dependent aldose reductase. Also shown in this pathway is the conversion of glucose to galactose vis a vis a different process to the ones described earlier. This pathway, called hexoneogenesis, allows mammary glands to produce galactose. It should be noted however, that despite the existence of this pathway of galactose production, the vast majority of galactose in breast milk is actually the result of direct uptake up from the blood, whereas only a small fraction, ~35%, is the result of this de novo process hexoneogenesis. Also depicted in this pathway are the conversions of other dietary di and tri-saccharides (raffinose, manninotriose, melibiose, stachyose) into galactose, glucose and fructose as well as and dietary sugar alcohols (melibitol, galactinol, galactosylglycerol) into sorbitol, myo-inositol, and glycerol.


Histidine Metabolism,Metabolic

Histidine is unique in that its biosynthesis is inherently linked to the pathways of nucleotide formation.  The biosynthesis of histidine in adults begins with the condensation of ATP and PRPP (phosphoribosyl pyrophosphate) to form N-5-phosphoribosyl 1-pyrophosphate (phosphoribosyl-ATP).  It is also worth noting that PRPP is the starting point for purine and pyrimidine biosynthesis.  Subsequent histidine biosynthetic steps (from phosphoribosyl-ATP onwards) likely take place in the intestinal microflora.  Elimination of the phosphate and the opening of the ring in phosphoribosyl-ATP forms phosphoribosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide (phosphoribosyl-formimino-AICAR-phosphate).  This is subsequently converted to 5-phosphoribulosyl-forminino-5-aminoimidazole-4-carboxamide ribonucleotide.  Cleavage of this intermediate results in the formation of imidazole glyercol phosphate and AICAR (aminoimidazolecarboxamide ribonucleotide) with glutamine playing a role as an amino group donor.  AICAR is recycled through the purine pathway while the imidazole glycerol phosphate is converted to imidazole acetal phosphate.  Transamination yields histidinol phosphate which is converted to histidinol and finally to histidine.  Histidine catabolism begins with release of the α-amino group catalyzed by histidase, leading to the deaminated product, urocanate.  Urocanate is converted to 4-imidazolone-5-propionate via the action of urocanate hydratase.  The latter product is then converted to N-formiminoglutamte via the action of imidazolone propionase.  The enzyme formiminotransferase cyclodeaminase then removes the formimino group to yield glutamate.  Because the end product of histidine catabolism is glutamate this makes histidine one of the glucogenic amino acids.  Another key feature of histidine catabolism is that it serves as a source of ring nitrogen to combine with tetrahydrofolate (THF), producing the 1-carbon THF intermediate known as N5-formiminoTHF.  The latter reaction is one of two routes to N5-formiminoTHF.  Decarboxylation of histidine in the intestine by bacteria gives rise to histamine.  Similarly, histamine arises in many tissues by the decarboxylation of histidine, which in excess causes constriction or dilation of various blood vessels.  Once histamine is generated it can be converted to several breakdown products including N-methylhistamine, imidazole acetaldehyde, methylimidazole acetaldehyde and methylimidazole-acetic acid.  Histidine is also a precursor for carnosine biosynthesis (via carnosine synthase), with beta-alanine being the rate limiting precursor.   Anserine can be synthesized either from carnosine via carnosine N-methyltransferase or from 1-methylhistidine via carnosine synthase.   Inversely, cytosolic non-specific dipeptidase catalyzes the synthesis of 1-methylhistidine from anserine.


Amino Sugar Metabolism,Metabolic

Amino sugars are sugar molecules containing an amine group. They make up many polysaccharides including, glycosaminoglycans or mucopolysaccharides.


Pyrimidine Metabolism,Metabolic

Pyrimidines are heterocyclic aromatic organic compounds similar to benzene and pyridine. Cytosine, thymine, and uracil are pyrimidine derivatives. Synthesis of the pyrimidines is less complex than that of the purines, since the base is much simpler This pathway depicts a number of processes including pyrimidine nucleotide biosynthesis, pyrimidine degradation and pyrimidine salvage. Pyrimidine nucleotide biosynthesis begins with carbamoyl phosphate. The carbamoyl phosphate used for pyrimidine nucleotide synthesis is derived from glutamine and bicarbonate and is catalyzed by carbamoyl phosphate synthetase II (CPS-II). Subsequently carbamoyl phosphate is incorporated into the pyrimidine nucleotide biosynthesis pathway through the action of aspartate transcarbamoylase, ATCase which generates carbamoyl aspartate. This is then converted to dihydroorotic acid via carbamoyl aspartate dehydrogenase, which is then converted to orotic acid via dihydroorotate dehydrogenase. The enzyme orotate phosphoribosyltransferase incorporate PRPP to produce orotidine monophosphate (OMP) which is converted to UMP (uridine monopohophsate) via orotidine-5’-phosphate carboxylase. Following completion of UMP synthesis it can be phosphorylated to UTP and utilized as a substrate for CTP synthase for the synthesis of CTP. Specifically, UMP is phosphorylated twice to yield UTP. The first phosphorylation is catalyzed by uridylate kinase and the second by ubiquitous nucleoside diphosphate kinase. Finally UTP is aminated by the action of CTP synthase, generating CTP. Uridine nucleotides are also the precursors for de novo synthesis of the thymine nucleotides. The de novo pathway to thymidine nucleotdie synthesis first requires the use of deoxyUMP from the metabolism of either UDP or CDP. The deoxyUMP is converted to deoxyTMP by the action of thymidylate synthase. The methyl group is donated by N5,N10-methylene THF. In order for the thymidylate synthase reaction to continue, THF must be regenerated from DHF. This is accomplished through the action of dihydrofolate reductase (DHFR). THF is then converted to N5,N10-THF via the action of serine hydroxymethyl transferase. The synthesis of pyrimidines differs in two significant ways from that of purines. First, the ring structure is assembled as a free base, not built upon PRPP. Second, there is no branch in the pyrimidine synthesis pathway. The salvage pathway to dTTP synthesis involves the enzyme thymidine kinase which can use either thymidine or deoxyuridine as a substrate. Uracil can be salvaged to form UMP through the concerted action of uridine phosphorylase and uridine kinase. Formation of dTMP, by salvage of dTMP requires the action of thymine phosphorylase and thymidine kinase while the salvage of deoxycytidine is catalyzed by deoxycytidine kinase. Deoxyadenosine and deoxyguanosine are also substrates for deoxycytidine kinase. In terms of the catabolism of pyrimidines, they are ultimately degraded to CO2, H2O, and urea. Cytosine can be broken down to uracil which can be further broken down to N-carbamoyl-beta-alanine and then to beta-alanine. Thymine is broken down into β-aminoisobutyrate. The β-alanine and β-aminoisobutyrate serve as -NH2 donors in the transamination of α-ketoglutarate to glutamate. A subsequent reaction converts the products to malonyl-CoA or methylmalonyl-CoA (which is converted to succinyl-CoA and can be shunted to the TCA cycle).


Nicotinate and Nicotinamide Metabolism,Metabolic

Nicotinate (niacin) and nicotinamide - more commonly known as vitamin B3 - are precursors of the coenzymes nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+). NAD+ synthesis occurs either de novo from amino acids, or a salvage pathway from nicotinamide. Most organisms use the de novo pathway whereas the savage pathway is only typically found in mammals. The specifics of the de novo pathway varies between organisms, but most begin by forming quinolinic acid (QA) from tryptophan (Trp) in animals, or aspartic acid in some bacteria (intestinal microflora) and plants.Nicotinate-nucleotide pyrophosphorylase converts QA into nicotinic acid mononucleotide (NaMN) by transfering a phosphoribose group. Nicotinamide mononucleotide adenylyltransferase then transfers an adenylate group to form nicotinic acid adenine dinucleotide (NaAD). Lastly, the nicotinic acid group is amidated to form a nicotinamide group, resulting in a molecule of nicotinamide adenine dinucleotide (NAD). Additionally, NAD can be phosphorylated to form NADP. The salvage pathway involves recycling nicotinamide and nicotinamide-containing molecules such as nicotinamide riboside. The precursors are fed into the NAD+ biosynthetic pathwaythrough adenylation and phosphoribosylation reactions. These compounds can be found in the diet, where the mixture of nicotinic acid and nicotinamide are called vitamin B3 or niacin. These compounds are also produced within the body when the nicotinamide group is released from NAD+ in ADP-ribose transfer reactions.


Purine Metabolism,Metabolic

Purines are heterocyclic aromatic organic compounds, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines, are the most widely distributed kind of nitrogen-containing heterocycle in nature. The two most important purines are adenine and guanine. Other notable purines are hypoxanthine, xanthine, theobromine, caffeine, uric acid and isoguanine. Purines are found in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. This pathway depicts a number of processes including purine nucleotide biosynthesis, purine degradation and purine salvage. The major site of purine nucleotide synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5'-monophosphate (IMP). IMP synthesis begins with 5-phospho-α-ribosyl-1-pyrophosphate, PRPP. Through a series of reactions utilizing ATP, tetrahydrofolate (THF) derivatives, glutamine, glycine and aspartate this pathway yields IMP. The rate limiting reaction is catalyzed by glutamine PRPP amidotransferase which drives the reaction with PRPP and glutamine yielding 5-phosphoribosylamine (PRA). 5-phosphoribosylamine is converted to glycinamide ribotide (GAR) then to formyglycinamide ribotide (FGAR). This set of reactions is catalyzed by a trifunctional enzyme containing GAR synthetase, GAR transformylase and AIR synthetase. FGAR is converted to formylglycinamidine-ribonucleotide (FGAM) by formylglycinamide synthase. FGAM is then converted by aminoimidzaole ribotide synthase to 5-aminoimidazole ribotide (AIR) then carboxylated by aminoimidazole ribotide carboxylase to carboxyaminoimidazole ribotide (CAIR). CAIR is then converted to succinylaminoimidazole carboxamide ribotide (SAICAR) by succinylaminoimidazole carboxamide ribotide synthase followed by conversion to AICAR (via adenylsuccinate lyase) then to FAICAR (via aminoimidazole carboxamide ribotide transformylase). FAICAR is finally converted to inosine monophosphate (IMP) by IMP cyclohydrolase. Because of the complexity of this synthetic process, the purine ring is actually composed of atoms derived from many different molecules. The N1 atom arises from the amine group of Asp, the C2 and C8 atoms originate from formate, the N3 and N9 atoms come from the amide group of Gln, the C4, C5 and N7 atoms come from Gly and the C6 atom comes from CO2. IMP represents a branch point for purine biosynthesis, because it can be converted into either AMP or GMP through two distinct reaction pathways. AMP is generated from IMP via adenylsuccinate synthetase (which adds aspartate) and adenylsuccinate lyase. GMP is generated via the action of IMP dehydrogenase and GMP synthase. Catabolism of purine nucleotides ultimately leads to the production of uric acid. Beginning from AMP, the enzymes AMP deaminase and nucleotidase work in concert to generate inosine. Alternately, AMP may be dephosphorylate by nucleotidase and then adenosine deaminase (ADA) converts the free adenosine to inosine. The enzyme purine nucleotide phosphorylase (PNP) converts inosine to hypoxanthine, while xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. GMP and XMP can also be converted to uric acid via the action of nucleotidase, PNP, guanine deaminase and xanthine oxidase. The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the salvage pathways. The free purine bases, adenine, guanine, and hypoxanthine, can be reconverted to their corresponding nucleotides by phosphoribosylation. Two key transferase enzymes are involved in the salvage of purines: adenosine phosphoribosyltransferase (APRT), which catalyzes the conversion of adenine to AMP and hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which catalyzes the conversion of hypoxanthine to IMP.


Fatty Acid Metabolism,Metabolic

Fatty acids constitute a large energy source for the body. The cellular membrane is also made up of fatty acids. During starvation times, fatty acids can provide energy to humans for numerous days. Fatty acid metabolism is also known as beta-oxidation. During metabolism, acetyl CoA is produced that can then enter the citric acid cycle. When ATP is needed, ATP may be generated by increasing fatty acid metabolism. Fatty acid metabolism is essentially the reverse reaction of fatty acid synthesis.


Beta Oxidation of Very Long Chain Fatty Acids,Metabolic

Fatty acid degradation in most organisms occurs primarily via the beta-oxidation cycle.  In mammals, beta-oxidation occurs in both mitochondria and peroxisomes, whereas plants and most fungi harbor the beta-oxidation cycle only in the peroxisomes.  However, the oxidation ceases at octanyl CoA.  It is believed that very long chain (greater than C-22) fatty acids undergo initial oxidation in peroxisomes which is followed by mitochondrial oxidation.  One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis.  Instead, the high-potential electrons are transferred to O2, which yields H2O2.  The enzyme catalase, found exclusively in peroxisomes, converts the hydrogen peroxide into water and oxygen.  Peroxisomal β-oxidation also requires enzymes specific to the peroxisome and to very long fatty acids.  There are three key differences between the enzymes used for mitochondrial and peroxisomal β-oxidation: beta-oxidation in the peroxisome requires the use of a peroxisomal carnitine acyltransferase (instead of carnitine acyltransferase I and II used by the mitochondria) for transport of the activated acyl group into the peroxisome.  The first oxidation step in the peroxisome is catalyzed by the enzyme acyl CoA oxidase.  The beta-ketothiolase used in peroxisomal beta-oxidation has an altered substrate specificity, different from the mitochondrial beta-ketothiolase.  In mitochondria, the beta-oxidation pathway includes four reactions that occur in repeating cycles with each fatty acid molecule.  In each cycle, a fatty acid is progressively shortened by two carbons as it is oxidized and its energy captured by the reduced energy carriers NADH and FADH2.  At the end of each cycle of four reactions, one acetyl-CoA two-carbon unit is released from the end of the fatty acid, which then goes through another round of beta-oxidation, continuing to oxidize and shorten even-chain fatty acids until they are entirely converted to acetyl-CoA.  The acetyl-CoA generated in beta-oxidation enters the TCA cycle, where it is further oxidized to CO2, producing more reduced energy carriers, NADH and FADH2.  These carriers produced in the TCA cycle, along with those produced directly in beta-oxidation, transfer their energy to the electron transport chain where they drive the creation of the proton gradient that supports mitochondrial ATP production.  Another destination of acetyl-CoA is the production of ketone bodies by the liver that are transported to tissues like the heart and brain for energy.


Folate Metabolism,Metabolic

The 1-carbon transformations require folic acid (folate). Folic acid participates in both the activation of single carbons as well as in the oxidation and reduction of single carbons. Folate-dependent single-carbon reactions are important in amino acid metabolism and in biosynthetic pathways leading to DNA, RNA, membrane lipids, and neurotransmitters. To carry out the transfer of 1-carbon units, NADPH must reduce folic acid two times in the cell. The pyrazine ring of the 6-methylpterin is reduced at each of the two N-C double bonds. More precisely, the pathway leading to the formation of tetrahydrofolate (THF) begins when folate (F) is reduced to dihydrofolate (DHF) which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. The resulting 5,6,7,8-tetrahydrofolate (THF) is the acceptor of 1-carbon groups. Tetrahydrofolate accepts methyl groups, usually from serine. The product, N5,N10-methylene-tetrahydrofolate, is the central compound in 1-carbon metabolism. Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Tetrahydrofolate can also accept a methyl group from the complete breakdown of glycine. The N5,N10-methylene-tetrahydrofolate can either donate its single-carbon group directly, be oxidized by NADP to the methenyl form, or be reduced by NADH to the methyl form. Depending on the biosynthetic pathway involved, any of these species can donate the 1-carbon group to an acceptor. The methylene form donates its methyl group during the biosynthesis of thymidine nucleotides for DNA synthesis, the methenyl form donates its group as a formyl group during purine biosynthesis, and the methyl form is the donor of the methyl group to sulfur during methionine formation. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. Another form of THF, formyl-THF or folinic acid) results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Finally, histidine can donate a single carbon to THF to form methenyl-THF.


Fatty Acid Elongation in Mitochondria,Metabolic

Cells typically contain large amounts of C18 and C20 fatty acids. Longer chain fatty acids are found in certain specialized tissues (myelin contains high amounts of C22 and C24 components). Even longer chain fatty acids are derived from either dietary sources or from elongation of C16-CoA or C18-CoA formed by the cytoplasmic fatty acid synthetase system. All of the fatty acids needed by the body can be synthesized from palmitate (C16:0) except the essential, polyunsaturated fatty acids such as linoleate and linolenate. To create longer, shorter, oxidized, reduced fatty acids, palmitic acid is subjected to enzymatic reactions by reductases, hydroxylases, elongases and mixed function oxidases. There are 3 major processes that modify palmitic acid: elongation, desaturation and hydroxylation. Elongation of fatty acids may occur at endoplasmic reticulum where fatty acid molecules of length up to C24 may be produced. Mitochondrial elongation may result in fatty acids up to C16 in length. Fatty acid elongation in mitochondria is essentially the reverse of beta-oxidation for fatty acid oxidation. In particular, both pathways make use of acetyl-CoA acyltransferase, 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase. The final step of fatty acid elongation uses enoyl-CoA reductase (not part of the beta-oxidation pathway). The elongation takes place in the mitochondrial matrix. In liver and kidney fatty acid elongation operates best in the presence of both NADH and NADPH, whereas in heart and skeletal muscle, only NADH is required. The mitochondrial pathway is important for elongating fatty acids containing 14 or fewer carbon atoms. Short chain fatty acids (SCFA) are fatty acids with aliphatic tails of less than six carbons. Medium chain fatty acids (MCFA) are fatty acids with aliphatic tails of 612 carbons. Long chain fatty acids (LCFA) are fatty acids with aliphatic tails longer than 12 carbons. Very Long chain fatty acids (VLCFA) are fatty acids with aliphatic tails longer than 22 carbons.


Alanine Metabolism,Metabolic

Alanine (L-Alanine) is an α-amino acid that is used for protein biosynthesis. Alanine transaminase can facilitate the reductive amination of pyruvate to produce alanine. L-Alanine can be converted to pyruvic acid by alanine aminotransferase 1 reversibly coupled with interconversion of oxoglutaric acid and L-glutamic acid. L-Alanine can also be produced by alanine-glyoxylate transaminase with coupled interconversion of glyoxylate and glycine. L-Alanine will be coupled with alanyl tRNA by alanyl-tRNA synthetase to perform protein biosynthesis. Alanine constitutes about 8% of human proteins. Under fasting conditions, alanine, derived from protein breakdown, can be converted to pyruvate and used to synthesize glucose via gluconeogenesis in the liver. Alternately, alanine, after conversion to pyruvate, can be fully oxidized via the TCA cycle in other tissues.


Citric Acid Cycle,Metabolic

The citric acid cycle, which is also known as the tricarboxylic acid cycle (TCA cycle) or the Krebs cycle, is a connected series of enzyme-catalyzed chemical reactions of central importance to all aerobic organisms (i.e. organisms that use oxygen for cellular respiration). The citric acid cycle is named after citrate or citric acid, a tricarboxylic acid that is both consumed and regenerated through this pathway. The citric acid cycle was discovered in 1937 by Hans Adolf Krebs while he worked at the University of Sheffield in England (PMID: 16746382). Krebs received the Nobel Prize for his discovery in 1953. Krebs’ extensive work on this pathway is also why the citric acid or TCA cycle is often referred to as the Krebs cycle. Metabolically, the citric acid cycle allows the release of energy (ultimately in the form of ATP) from carbohydrates, fats, and proteins through the oxidation of acetyl-CoA. The citric acid cycle also produces CO2, the precursors for several amino acids (aspartate, asparagine, glutamine, proline) and NADH – all of which are used in other important metabolic pathways, such as amino acid synthesis and oxidative phosphorylation (OxPhos). The net yield of one “turn” of the TCA cycle in terms of energy-containing compounds is one GTP, one FADH2, and three NADH molecules.  The NADH molecules are used in oxidative phosphorylation to generate ATP. In eukaryotes, the citric acid cycle occurs in the mitochondrial matrix. In prokaryotes, the citric acid cycle occurs in the cytoplasm.  In eukaryotes, the citric acid or TCA cycle has a total of 10 steps that are mediated by 8 different enzymes.  Key to the whole cycle is the availability of acetyl-CoA. One of the primary sources of acetyl-CoA is from the breakdown of glucose (and other sugars) by glycolysis. This process generates pyruvate. Pyruvate is decarboxylated by pyruvate dehydrogenase to generate acetyl-CoA. The citric acid cycle begins with acetyl-CoA transferring its two-carbon acetyl group to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate) through the enzyme citrate synthase. The resulting citrate is then converted to cis-aconitate and then isocitrate via the enzyme aconitase.  The resulting isocitrate then combines with NAD+ to form oxalosuccinate and NADH, which is then converted into alpha-ketoglutarate (and CO2) through the action of the enzyme known as isocitrate dehydrogenase. The resulting alpha-ketoglutarate combines with NAD+ and CoA-SH to produce succinyl-CoA, NADH, and CO2. This step is mediated by the enzyme alpha-ketoglutarate dehydrogenase. The resulting succinyl-CoA combines with GDP and organic phosphate to produce succinate, CoA-SH, and GTP. This phosphorylation reaction is performed by succinyl-CoA synthase. The resulting succinate then combines with ubiquinone to produce two compounds, fumarate and ubiquinol through the action of the enzyme succinate dehydrogenase.  The resulting fumarate is then hydrated by the enzyme known as fumarase to produce malate. The resulting malate is oxidized via NAD+ to produce oxaloacetate and NADH. This oxidation reaction is performed by malate dehydrogenase.  The resulting oxaloacetate can then combine with acetyl-CoA and the TCA reaction cycle begins again. Overall, in the citric acid cycle, the starting six-carbon citrate molecule loses two carboxyl groups as CO2, leading to the production of a four-carbon oxaloacetate. The two-carbon acetyl-CoA that is the “fuel” for the TCA cycle can be generated by several metabolic pathways including glucose metabolism, fatty acid oxidation, and the metabolism of amino acids.  The overall reaction for the citric acid cycle is as follows: acetyl-CoA + 3 NAD+ + FAD + GDP + P + 2H2O = CoA-SH + 3NADH + FADH2 + 3H+ + GTP + 2CO2. Many molecules in the citric acid cycle serve as key precursors for other molecules needed by cells.  The citrate generated via the citric acid cycle can serve as an intermediate for fatty acid synthesis; alpha-ketoglutarate can serve as a precursor for glutamate, proline, and arginine; oxaloacetate can serve as a precursor for aspartate and asparagine; succinyl-CoA can serve as a precursor for porphyrins; and acetyl-CoA can serve as a precursor fatty acids, cholesterol, vitamin D, and various steroid hormones. There are several variations to the citric acid cycle that are known. Interestingly, most of the variation lies with the step involving succinyl-CoA production or conversion.  Humans and other animals have two different types of succinyl-CoA synthetases. One produces GTP from GDP, while the other produces ATP from ADP (PMID: 9765291). On the other hand, plants have a succinyl-CoA synthetase that produces ATP (ADP-forming succinyl-CoA synthetase) (Jones RC, Buchanan BB, Gruissem W. (2000). Biochemistry & molecular biology of plants (1st ed.). Rockville, Md: American Society of Plant Physiologists. ISBN 0-943088-39-9.). In certain acetate-producing bacteria, such as Acetobacter aceti, an enzyme known as succinyl-CoA:acetate CoA-transferase performs this conversion (PMID: 18502856) while in Helicobacter pylori succinyl-CoA:acetoacetate CoA-transferase is responsible for this reaction (PMID: 9325289). The citric acid cycle is regulated in a number of ways but the primary mechanism is by product inhibition. For instance, NADH inhibits pyruvate dehydrogenase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and citrate synthase. Acetyl-CoA inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits alpha-ketoglutarate dehydrogenase and citrate synthase.  Additionally, ATP inhibits citrate synthase and alpha-ketoglutarate dehydrogenase. Calcium is another important regulator of the citric acid cycle. In particular, it activates pyruvate dehydrogenase phosphatase, which then activates pyruvate dehydrogenase. Calcium also activates isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase (PMID: 171557).


Starch and Sucrose Metabolism,Metabolic

The digestion of starch begins with the action of amylase enzymes secreted in the saliva and small intestine, which convert it to maltotriose, maltose, limit dextrins, and some glucose.  Digestion of the limit dextrins and disaccharides, both dietary and starch-derived, to monosaccharides – glucose, galactose, and fructose – is accomplished by enzymes located on the luminal surfaces of enterocytes lining the microvilli of the small intestine.  Once released from starch or once ingested, sucrose can be degraded into beta-D-fructose and alpha-D-glucose via lysosomal alpha-glucosidase or sucrose-isomaltase.  Beta-D-fructose can be converted to beta-D-fructose-6-phosphate by glucokinase and then to alpha-D-glucose-6-phosphate by the action of glucose phosphate isomerase.  Phosphoglucomutase 1 can then act on alpha-D-glucose-6-phosphate (G6P) to generate alpha-D-glucose-1-phosphate.  Alpha-D-glucose-1-phosphate (G6P) has several possible fates.  It can enter into gluconeogenesis, glycolysis or the nucleotide sugar metabolism pathway.  UDP-glucose pyrophosphorylase 2 can convert alpha-D-glucose-1-phosphate into UDP-glucose, which can then be converted to UDP-xylose or UDP-glucuronate and, eventually to glucuronate.  UDP-glucose can also serve as a precursor to the synthesis of glycogen via glycogen synthase.  More specifically, glycogen is synthesized from monomers of UDP-glucose by the enzyme glycogen synthase, which progressively lengthens the glycogen chain with (α1→4) bonded glucose.  As glycogen synthase can only lengthen an existing chain, the protein glycogenin is needed to initiate the synthesis of glycogen.  The glycogen-branching enzyme, amylo (α1→4) to (α1→6) transglycosylase, catalyzes the transfer of a terminal fragment of 6-7 glucose residues from a nonreducing end to the C-6 hydroxyl group of a glucose residue deeper into the interior of the glycogen molecule.  The branching enzyme can only act upon a branch having at least 11 residues, and the enzyme may transfer to the same glucose chain or adjacent glucose chains.  Another enzyme known as starch phosphorylase or glycogen phosphorylase can also convert starch into glycogen.  Glycogen functions as the secondary short term energy storage in animal cells.  It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach.  Glycogen is the analogue of starch, a less branched glucose polymer in plants, and is commonly referred to as animal starch, having a similar structure to amylopectin.  Glycogen is found in the form of granules in the cytosol in many cell types, and plays an important role in the glucose cycle.  Glycogen is cleaved from the nonreducing ends of the chain by the enzyme glycogen phosphorylase to produce monomers of glucose-1-phosphate that is then converted to glucose 6-phosphate (G6P).  G6P can continue on the glycolysis pathway and be used as fuel or G6P can enter the pentose phosphate pathway via the enzyme glucose-6-phosphate dehydrogenase to produce NADPH and 5-carbon sugars or, in the liver and kidney, G6P can be dephosphorylated back to glucose by the enzyme glucose 6-phosphatase.  This is the final step in the gluconeogenesis pathway.


Urea Cycle,Metabolic

About 80% of the body’s excreted nitrogen is in the form of urea which is also largely made in the liver, in a series of reactions that are distributed between the mitochondrial matrix and the cytosol. The series of reactions that form urea is known as the Urea Cycle (Ornithine Cylce) or the Krebs-Henseleit Cycle. The essential features of the urea cycle reactions and their metabolic regulation are as follows: Arginine from the diet or from protein breakdown is cleaved by the cytosolic enzyme arginase, generating urea and ornithine. In subsequent reactions of the urea cycle a new urea residue is built on the ornithine, regenerating arginine and perpetuating the cycle. Ornithine arising in the cytosol is transported to the mitochondrial matrix, where ornithine transcabamoylase catalyzes the condensation of ornithine with carbamoyl phosphate, producing citrulline. The energy for the reaction is provided by the high-energy anhydride of carbamoyl phosphate. The product, citrulline, is then transported to the cytosol, where the remaining reactions of the cycle take place. The synthesis of citrulline requires a prior activation of carbon and nitrogen as carbamoyl phosphate (CP). The activation step requires 2 equivalents of ATP and the mitochondrial matrix enzyme carbamoyl phosphate synthetase-I (CPS-I). In a 2-step reaction, catalyzed by cytosolic argininosuccinate synthetase, citrulline and aspartate are condensed to form argininosuccinate. The reaction involves the addition of AMP (from ATP) to the amido carbonyl of citrulline, forming an activated intermediate on the enzyme surface (AMP-citrulline), and the subsequent addition of aspartate to form argininosuccinate. Arginine and fumarate are produced from argininosuccinate by the cytosolic enzyme argininosuccinate lyase. In the final step of the cycle arginase cleaves urea from aspartate, regenerating cytosolic ornithine, which can be transported to the mitochondrial matrix for another round of urea synthesis. The fumarate, generated via the action of arginiosuccinate lyase, is reconverted to aspartate for use in the argininosuccinate synthetase reaction.


Pyruvate Metabolism,Metabolic

Pyruvate is an intermediate compound in the metabolism of fats, proteins, and carbohydrates. It can be formed from glucose via glycolysis or the transamination of alanine. It can be converted into Acetyl-CoA to be used as the primary energy source for the TCA cycle, or converted into oxaloacetate to replenish TCA cycle intermediates. Pyruvate can also be used to synthesize carbohydrates, fatty acids, ketone bodies, alanine, and steroids. In conditions of inssuficient oxygen or in cells with few mitochondria, pyruvate is reduced to lactate in order to re-oxidize NADH back into NAD+Pyruvate participates in several key reactions and pathways. In glycolysis, phosphoenolpyruvate (PEP) is converted to pyruvate by pyruvate kinase in an highly exergonic and irreversible reaction. In gluconeogenesis, pyruvate carboxylase and PEP carboxykinase are needed to catalyze the conversion of pyruvate to PEP. In fatty acid synthesis, the pyruvate dehydrogenase complex decarboxylates pyruvate to produce acetyl-CoA. In gluconeogenesis, the carboxylation by pyruvate carboxylase produces oxaloacetate. The fate of pyruvate depends on the cell energy charge. In cells or tissues with a high energy charge pyruvate is directed toward gluconeogenesis, but when the energy charge is low pyruvate is preferentially oxidized to CO2 and H2O in the TCA cycle, with generation of 15 equivalents of ATP per pyruvate. The enzymatic activities of the TCA cycle are located in the mitochondrion. When transported into the mitochondrion, pyruvate encounters two principal metabolizing enzymes: pyruvate carboxylase (a gluconeogenic enzyme) and pyruvate dehydrogenase (PDH). With a high cell-energy charge, acetyl-CoA, is able allosterically to activate pyruvate carboxylase, directing pyruvate toward gluconeogenesis. When the energy charge is low CoA is not acylated, pyruvate carboxylase is inactive, and pyruvate is preferentially metabolized via the PDH complex and the enzymes of the TCA cycle to CO2 and H2O.


Tryptophan Metabolism,Metabolic

This pathway depicts the metabolic reactions and pathways associated with tryptophan metabolism in animals. Tryptophan is an essential amino acid. This means that it cannot be synthesized by humans and other mammals and therefore must be part of the diet. Unlike animals, plants and microbes can synthesize tryptophan from shikimic acid or anthranilate. As one of the 20 proteogenic amino acids, tryptophan plays an important role in protein biosynthesis through the action of tryptophanyl-tRNA synthetase. As shown in this pathway, tryptophan can be linked to the tryptophanyl-tRNA via either the mitochondrial or cytoplasmic tryptophan tRNA ligases. Also shown in this pathway map is the conversion of tryptophan to serotonin (a neurotransmitter). In this process, tryptophan is acted upon by the enzyme tryptophan hydroxylase, which produces 5-hydroxytryptophan (5HTP). 5HTP is then converted into serotonin (5-HT) via aromatic amino acid decarboxylase. Serotonin, in turn, can be converted into N-acetyl serotonin (via serotonin-N-acetyltransferase) and then melatonin (a neurohormone), via 5-hydroxyindole-O-methyltransferase. The melatonin can be converted into 6-hydroxymelatonin via the action of cytochrome P450s in the endoplasmic reticulum. Serotonin has other fates as well. As depicted in this pathway it can be converted into N-methylserotonin via Indolethylamine-N-methyltransferase (INMT) or it can be converted into formyl-5-hydroxykynurenamine via indoleamine 2,3-dioxygenase. Serotonin may also be converted into 5-methoxyindoleacetate via a series of intermediates including 5-hydroxyindoleacetaldehyde and 5-hydroxyindoleacetic acid. Tryptophan can be converted or broken down into many other compounds as well. It can be converted into tryptamine via the action of aromatic amino acid decarboxylase. The resulting tryptamine can then be converted into indoleacetaldehyde via kynurenine 3-monooxygenase and then into indoleacetic acid via the action of aldehyde dehydrogenase. Tryptophan also leads to the production of a very important compound known as kynurenine. Kynurenine is synthesized via the action of tryptophan 2,3-dioxygnase, which produces N-formylkynurenine. This compound is converted into kynurenine via the enzyme known as kynurenine formamidase (AFMID). Kynurenine has at least 3 fates. First, kynurenine can undergo deamination in a standard transamination reaction yielding kynurenic acid. Secondly, kynurenine can undergo a series of catabolic reactions (involving kynureninase and kynurenine 3-monooxygenase) producing 3-hydroxyanthranilate plus alanine. In this reaction, kynureninase catabolizes the conversion of kynurenine into anthranilic acid while kynurenine—oxoglutarate transaminase (also known as kynurenine aminotransferase or glutamine transaminase K, GTK) catabolizes its conversion into kynurenic acid. The action of kynurenine 3-hydroxylase on kynurenic acid leads to 3-hydroxykynurenine. The oxidation of 3-hydroxyanthranilate converts it into 2-amino-3-carboxymuconic 6-semialdehyde, which has two fates. It can either degrade to form acetoacetate or it can cyclize to form quinolate. Most of the body’s 3-hydroxyanthranilate leads to the production of acetoacetate (a ketone body), which is why tryptophan is also known as a ketogenic amino acid. An important side reaction in the liver involves a non-enzymatic cyclization into quinolate followed by transamination and several rearrangements to yield limited amounts of nicotinic acid, which leads to the production of a small amount of NAD+ and NADP+.


Fructose and Mannose Degradation,Metabolic

Fructose and mannose are monosaccharides that can be found in many foods. Fructose can join with glucose to form sucrose. Mannose can be converted to glucose. Both may be used as food sweeteners. Fructose is well absorbed, especially in the presence of glucose. Fructose causes less of an insulin response compared to glucose and thus may be a preferred sugar for diabetics. In contrast to fructose, humans do not metabolize mannose well with the majority of it being excreted unchanged. Mannose in the urine can be beneficial in treating urinary tract infections caused be E. coli. However, mannose can be detrimental to humans by causing diabetic complications.


Ubiquinone Biosynthesis,Metabolic

Ubiquinone is also known as coenzyme Q10. It is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the isoprenyl chemical subunits. Ubiquinone is a carrier of hydrogen atoms (protons plus electrons) and functions as an ubiquitous coenzyme in redox reactions, where it is first reduced to the enzyme-bound intermediate radical semiquinone and in a second reduction to ubiquinol (Dihydroquinone; CoQH2). Ubiquinone is not tightly bound or covalently linked to any known protein complex but is very mobile. In eukaryotes ubiquinones were found in the inner mito-chondrial membrane and in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes and peroxisomes. The benzoquinone portion of Coenzyme Q10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is also used for the first steps of cholesterol biosynthesis. The enzyme para-hydroxybenzoate polyprenyltransferase catalyzes the condensation of p-hydroxybenzoate with polyprenyl diphosphate to generate ubiquinone.


Biotin Metabolism,Metabolic

Biotin is a vitamin that is an essential nutrient for humans. Biotin can be absorbed from consuming various foods such as: legumes, soybeans, tomatoes, romaine lettuce, eggs, cow's milk, oats and many more. Biotin acts as a cofactor for enzymes to catalyze carboxylation reactions involved in gluconeogenesis, amino acid catabolism and fatty acid metabolism. Biotin deficiency has been associated with many human diseases. These diseases may be caused by dysfunctional biotin metabolism due to enzyme deficiencies. Some research suggests biotin may play a role in transcription regulation or protein expression which may lead to biotin related diseases.


Aspartate Metabolism,Metabolic

Aspartate is synthesized by transamination of oxaloacetate by aspartate aminotransferase or amino acid oxidase. Aspartyl-tRNA synthetase can then couple aspartate to aspartyl tRNA for protein synthesis. The aspartate content in human proteins is about 7%. Asparagine synthase can convert aspartate to the polar amino acid asparagine. Aspartate is also a precursor for cellular signaling compounds such as, N-acetyl-aspartate, beta-alanine, adenylsuccinate, arginino-succinate and N-carbamoylaspartate. Aspartate is also a metabolite in the urea cycle and involved in gluconeogenesis. Additionally, aspartate carries the reducing equivalents in the mitochondrial malate-aspartate shuttle, which utilizes the ready interconversion of aspartate and oxaloacetate. The conjugate base of L-aspartic acid, aspartate, also acts as an excitatory neurotransmitter in the brain which activates NMDA receptors.


Androgen and Estrogen Metabolism,Metabolic

This pathway describes the inactivation and catabolism of male (androgen) and female (estrogen) hormones. Many steroid hormones are transformed by sulfatases, dehydrogenases and glucuronide transferases to enhance their solubility and to facilitate their elimination. Inactivation refers to the metabolic conversion of a biologically active compound into an inactive one. Peripheral inactivation (e.g. by liver enzymes) is required to ensure steady-state levels of plasma androgens and estrogens. Specifically, if an androgen or estrogen is to act as a " chemical signal ", its half-life in the circulation must be limited, so that any change in secretion rate is immediately reflected by a change in its plasma concentration. But hormone inactivation can also occur in target tissues, notably after the hormone has triggered the relevant biological effects in order to ensure termination of hormone action. The main site of peripheral androgen/estrogen inactivation and catabolism is the liver, but some catabolic activity also occurs in the kidneys. Inactive androgens and estrogens are mainly eliminated as urinary (mostly conjugated) metabolites. This elimination requires conversion to hydrophilic compounds in order to ensure their solubility in biological fluids at rather high concentrations. Depending on the structure of the starting steroid there may be: 1) Reduction of a double bond at C-4 and reduction of an oxo(keto) group at C-3 to a secondary alcoholic group; 2) Reduction of an oxo group at C-20 to a secondary alcoholic group; 3) Oxidation of a 17ß-hydroxyl group; 4) Further hydroxylations at various positions of the steroid nucleus (e.g. 7-hydroxylation of 5a-reduced androgens) or 5) Conjugation (sulphate and/or glucuronide derivatives).


Riboflavin Metabolism,Metabolic

Riboflavin (vitamin B2) is an important part of the enzyme cofactors FAD (flavin-adenine dinucleotide) and FMN (flavin mononucleotide).  The name "riboflavin" actually comes from "ribose" and "flavin".  Like the other B vitamins, riboflavin is needed for the breaking down and processing of  ketone bodies, lipids, carbohydrates, and proteins.  Riboflavin is found in many different foods, such as meats and vegetables.As the digestion process occurs, many different flavoproteins that come from food are broken down and riboflavin is reabsorbed. The reverse reaction is mediated by acid phosphatase 6. FMN can be turned into to FAD via FAD synthetase, while the reverse reaction is mediated by nucleotide pyrophosphatase.  FAD and FMN are essential hydrogen carriers and are involved in over 100 redox reactions that take part in energy metabolism.


Ketone Body Metabolism,Metabolic

Ketone bodies are consisted of acetone, beta-hydroxybutyrate and acetoacetate. In liver cells' mitochondria, acetyl-CoA can synthesize acetoacetate and beta-hydroxybutyrate; and spontaneous decarboxylation of acetoacetate will form acetone. Metabolism of ketone body (also known as ketogenesis) contains several reactions. Acetoacetic acid (acetoacetate) will be catalyzed to form acetoacetyl-CoA irreversibly by 3-oxoacid CoA-transferase 1 that also coupled with interconversion of succinyl-CoA and succinic acid. Acetoacetic acid can also be catalyzed by mitochondrial D-beta-hydroxybutyrate dehydrogenase to form (R)-3-Hydroxybutyric acid with NADH. Ketogenesis occurs mostly during fasting and starvation.  Stored fatty acids will be broken down and mobilized to produce large amount of acetyl-CoA for ketogenesis in liver, which can reduce the demand of glucose for other tissues. Acetone cannot be converted back to acetyl-CoA; therefore, they are either breathed out through the lungs or excreted in urine.


Glutamate Metabolism,Metabolic

Glutamate is one of the non-essential amino acids that is produced by the body. Glutamate is precursor for many nucleic acids and proteins in addition to its role in the central nervous system. It is an excitatory neurotransmitter and has a role in neuronal plasticity, affecting memory and learning.  Glutamate plays a role in numerous metabolic pathways. Dysfunctional glutamate metabolism may cause disorders such as: gyrate atrophy, hyperammonemia, γ-hydoxybutyric aciduria, hemolytic anemia, and 5-oxoprolinuria.


Butyrate Metabolism,Metabolic

Butyrate metabolism (Butanoate metabolism) describes the metabolic fate of a number of short chain fatty acids or short chain alcohols that are typically produced by intestinal fermentation. Many of these molecules are eventually used in the production of ketone bodies, the creation of short-chain lipids or as precursors to the citrate cycle, glycolysis or glutamate synthesis. The molecule for which this pathway is named, butyric acid, is a four-carbon fatty acid that is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber). It is found in rancid butter, parmesan cheese, and vomit, and has an unpleasant odor and acrid taste, with a sweet aftertaste (similar to ether).


Retinol Metabolism,Metabolic

Retinol is part of the vitamin A family, and is known as vitamin A1, and in a dietary context it is a type of preformed vitamin A. As with other preformed vitamin A's, it can be obtained from animal sources, with the highest concentrations coming from animal liver, with other sources being fish and dairy products. Other forms of vitamin A include retinal, its aldehyde form, retinoic acid, its acid form, and reinyl ester, its ester form. Additionally, herbivores and omnivores can obtain provitamin A from things such as alpha-, beta- and gamma-carotene, which can be converted to retinol as needed by the body.Retinol can be used in the body to form retinyl ester via diacylglycerol O-acyltransferase 1 and acyl-CoA wax akcohol acyltransferase 1 which both use acetyl-CoA as a reactant and produce CoA in addition to the retinyl ester. IT can also be produced by lecithin retinol acyltransferase, which uses a phosphatidylcholine molecule, and produces glycerophosphocholine. All of these reactions take place in the endoplasmic reticulum. Retinyl ester can also be converted back to retinol by patatin-like phospholipase domain-containing protein 4 as the enzyme in a reaction that also converts a diacylglycerol to a triacylglycerol. Alternately, retinyl ester can interact with retinoid isomerohydrolase to form 11-cis-retinol.11-cis-retinol can be converted to retinyl palmitate by either diacylglycerol O-acyltransferase 1 or acyl-CoA wax alcohol acyltransferase 1 in the endoplasmic reticulum, which both add the acetyl group onto 11-cis-retinol, forming CoA as a side product. Alternatively, retinyl palmitate can be formed by lecithin retinol acyltransferase, which takes a molecule of phosphatidylcholine, and produces glycerophosphocholine in addition to the retinyl palmitate.Rhodopsin, a photosensitive protein found in the retina, can be converted to bathorhodopsin, which has previously been known as prelumirhodopsin. This conversion is caused by the absorption of light into the retinal portion of the protein complex, which then isomerizes, forcing the protein to change shape to accomodate this. Bathorhodopsin almost immediately converts to lumirhodopsin, which then converts to metarhodopsin, and at this point, the retinal is in its all-trans configuration. All-trans retinal can also be formed from 11-cis-retinaldehyde, also known as 11-cis-retinal, via dehydrogenase/reductase SDR family member 4 or retinol dehydrogenase 12 in the cell, as well as retinol dehydrogenases 8 and 16, short-chain dehydrogenase/reductase 3 or dehydrogenase/reductase SRD family member 9 in the endoplasmic reticulum. Two molecules of retinal can also be formed from beta-carotene, after its interaction with betabeta-carotene 15,15'-monooxygenase, or from retinol via retinol dehydrogenase 11 in the endoplasmic reticulum. Additionally, 11-cis-retinaldehyde can reversibly form all-trans retinal via interaction with alcohol dehydrogenase 1A. 11-cis-retinaldehyde is also in the conformation found in rhodopsin, and can be used to create more rhodopsin complexes. 11-cis-retinaldehyde can also be converted to 11-cis-retinol by retinol dehydrogenase in the endoplasmic reticulum.Retinol can also isomerize and form 9-cis-retinol, which can then be reversibly oxidized to form 9-cis-retinal by interacting with either retinol dehydrogenase 11 or dehydrogenase/reductase SDR family member 4. 9-cis-retinal can then be further oxidized to 9-cis-retinoic acid by retinal dehydrogenase 1 or 2. 9-cis-retinoic acid can also be formed from the isomerization of all-trans retinoic acid, which in turn is formed by the oxidation of retinol by either of retinal dehydrogenase 1 or 2.All-trans retinoic acid can also be glucuronidated to form retinoyl b-glucuronide, in a reaction catalyzed by a multiprotein chaperone complex including UDP-glucuronosyltransferase 1-1 in the endoplasmic reticulum. Finally, in the endoplasmic reticulum, all-trans-retinoic acid can undergo epoxidation to form all-trans-5,6-epoxyretinoic acid by interaction with a complex of cytochrome P450 proteins, or hydroxylated to either 4-hydroxyretinoic acid or all-trans-18-hydroxyretinoic acid by cytochrome P450 26A1. In one last reqction, 4-hydroxyretinoic acid can be oxidized once again by cytochrome P450 26A1 to form 4-oxo-retinoic acid.


Arachidonic Acid Metabolism,Metabolic

This pathway describes the production and subsequent metabolism of arachidonic acid, an omega-6 fatty acid. In resting cells arachidonic acid is present in the phospholipids (especially phosphatidylethanolamine and phosphatidylcholine) of membranes of the body’s cells, and is particularly abundant in the brain. Typically a receptor-dependent event, requiring a transducing G protein, initiates phospholipid hydrolysis and releases the fatty acid into the intracellular medium. Three enzymes mediate this deacylation reaction including phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD). Once released, free arachidonate has three possible fates: 1) reincorporation into phospholipids, 2) diffusion outside the cell, and 3) metabolism. Arachidonate metabolism is carried out by three distinct enzyme classes: cyclooxygenases, lipoxygenases, and cytochrome P450’s. Specifically, the enzymes cyclooxygenase and peroxidase lead to the synthesis of prostaglandin H2, which in turn is used to produce the prostaglandins, prostacyclin, and thromboxanes. The enzyme 5-lipoxygenase leads to 5-HPETE, which in turn is used to produce the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins. Some arachidonic acid is converted into midchain HETEs, omega-chain HETEs, dihydroxyeicosatrienoic acids (DHETs), and epoxyeicosatrienoic acids (EETs) by cytochrome P450 epoxygenase hydroxylase activity. Several products of these pathways act within neurons to modulate the activities of ion channels, protein kinases, ion pumps, and neurotransmitter uptake systems, affecting processes such as cellular proliferation, inflammation, and hemostasis. The newly formed eicosanoids may also exit the cell of origin and bind to G-protein-coupled receptors present on nearby neurons or glial cells.


Thiamine Metabolism,Metabolic

Thiamin(e), also known as vitamin B1, is known to play a fundamental role in energy metabolism. It consists of a pyrimidine ring (2,5-dimethyl-6-aminopyrimidine) and a thiazolium ring (4-methyl-5-hydroxy ethyl thiazole) joined by a methylene bridge. Thiamine is found in a wide variety of foods at low concentrations. Yeast and pork are the most highly concentrated sources of thiamine. Cereal grains, however, are generally the most important dietary sources of thiamine, by virtue of their ubiquity. Of these, whole grains contain more thiamine than refined grains. Thiamine is released by the action of phosphatase and pyrophosphatase in the upper small intestine. At low concentrations the process is carrier mediated and at higher concentrations, absorption occurs via passive diffusion. Active transport is greatest in the jejunum and ileum (it is inhibited by alcohol consumption and by folic deficiency). The majority of thiamine in serum is bound to proteins, mainly albumin. Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion. About 80% of intracellular thiamine is phosphorylated and most is bound to proteins. Thiamine and its acid metabolites (2-methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid and thiamine acetic acid) are excreted principally in the urine. Thiamine is mainly the transport form of the vitamin, while the active forms are phosphorylated thiamine derivatives. There are four known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP) and adenosine thiamine diphosphate (AThDP). Thiamine monophosphate (TMP) is an intermediate to facilitate the synthesis of free thiamine to thiamine diphosphate and triphosphate. The synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate (TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinase. TPP activates decarboxylation of pyruvate in the pyruvate dehydrogenase complex. This complex is a group of enzymes and cofactors that form acetyl CoA that condenses with oxaloacetate to form citrate, the first component of the citric acid cycle.


Piroxicam Action Pathway,Drug Action

Piroxicam (also named Feldene or Piroxicamum) is a nonsteroidal anti-inflammatory drug. Piroxicam can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of piroxicam. Piroxicam can prevent movement of leukocytes to inflammation site so that thromboxane A2 can't be produced.


Chlorothiazide Action Pathway,Drug Action

Chlorothiazide (also known as Diuril) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.


Ibandronate Action Pathway,Drug Action

The action of ibandronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting farnesyl pyrophosphate (FPP) synthase, an enzyme in the mevalonate pathway of cholesterol biosynthesis. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signaling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.


Polythiazide Action Pathway,Drug Action

Polythiazide (also known as Renese or Drenusil) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.


Methyclothiazide Action Pathway,Drug Action

Methyclothiazide (also known as Enduron or Methyclothiazid) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.


Simvastatin Action Pathway,Drug Action

Simvastatin, the methylated form of lovastatin, is an inactive lactone that is metabolized in vivo to β,δ-dihydroxy acid, its most potent metabolite. Cytochrome P450 (CYP) enzymes, CYP3A4, CYP3A5, and CYP2C8, have been implicated in this activation step; CYP3A4/5 are responsible for ≥ 80% of simvastatin metabolism while CYP2C8 (not shown in pathway) contributes to ≤ 20% of its metabolism. The simvastatin hydroxy acid inhibits cholesterol synthesis via the mevalonate pathway by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase, a hepatic microsomal enzyme, is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis by this pathway. The active hydroxy acid is structurally similar to the reduced reaction intermediate and competes with HMG-CoA for binding to HMG-CoA reductase. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.


Acetylsalicylic Acid Action Pathway,Drug Action

Acetylsalicylic acid, also known as ASA or aspirin, belongs to a class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). In addition to its anti-inflammatory properties, aspirin also acts as an analgesic, antipyretic and antithrombotic agent. Like most other NSAIDs, aspirin exerts its therapeutic effects by inhibiting prostaglandin G/H synthase 1 and 2, better known as cyclooxygenase-1 and -2 or simply COX-1 and -2. COX-1 and -2 catalyze the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor to a number of other prostaglandins, such as prostaglandin E2, involved in pain, fever and inflammation. The antipyretic properties of aspirin arise from inhibition of prostaglandin E2 synthesis in the preoptic region of the hypothalamus. Interference with adhesion and migration of granulocytes, polymorphonuclear leukocytes and macrophages at sites of inflammation account for its anti-inflammatory effects. The analgesic effects of aspirin likely occur due to peripheral action at the site of injury and possibly within the CNS.  Aspirin is unique from other NSAIDs in that it is an irreversible COX inhibitor. Aspirin irreversibly acetylates a serine side chain of COX rendering the enzyme inactive. Enzyme activity can only be regained by production of more cyclooxygenase. This unique property of aspirin and its higher selectivity for COX-1 over COX-2 makes it an effective antiplatelet agent. Platelets contain COX-1, a key enzyme in the production thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation. Since platelets lack the ability to make more enzyme, TXA2 production is inhibited for the lifetime of the platelet (approximately 8 – 12 days). Aspirin is commonly used at low doses to prevent cardiovascular events such as strokes and heart attacks. At higher doses, aspirin may be used as an analgesic, anti-inflammatory and antipyretic. Aspirin may cause gastric irritation and bleeding by inhibiting the synthesis of prostaglandins that enhance and maintain the protective gastric mucous layer.


Etodolac Action Pathway,Drug Action

Etodolac is a non-steroidal anti-inflammatory drug (NSAID) that can be used to treat rheumatoid arthritis and osteoarthritis. Most NSAIDs are non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitors that act on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. NSAIDs antagonize COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of NSAIDs occur as a result of decreased prostaglandin synthesis. Etodolac was previously thought to be a non-selective COX inhibitor; however, it is now know that it is five to fifty times more selective for COX-2 than COX-1. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of etodolac.  The latter portion of this figure depicts etodolac’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur.  Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Etodolac preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market.


Ketoprofen Action Pathway,Drug Action

Ketoprofen (also known as (RS)-2-(3-benzoylphenyl)-propionic acid) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat rheumatoid arthritis, osteoarthritis, dysmenorrhea, and to alleviate moderate pain.. Ketoprofen can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Because of hypothalamus action, antipyretic effects may occur which will lead to vasodilation, increased peripheral blood flow and subsequent heat dissipation.


Ibuprofen Action Pathway,Drug Action

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) used for its analgesic, antipyretic and anti-inflammatory properties. Like most NSAIDs, ibuprofen is a non-selective inhibitor of prostaglandin G/H synthase 1 and 2, better known as cyclooxygenase 1 and 2 or simply COX-1 and -2. COX catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Ibuprofen antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. The analgesic, antipyretic and anti-inflammatory effects of ibuprofen occurs as a result of decreased prostaglandin synthesis. Ibuprofen is slightly more potent than aspirin and produces analgesic effects at lower doses than aspirin. Unlike aspirin, ibuprofen is a reversible COX inhibitor and thus it is not used as an antiplatelet agent.


Rofecoxib Action Pathway,Drug Action

Rofecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a highly selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, rofecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precursor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Rofecoxib antagonizes COX-2 by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors such as celecobix and valdecoxib, rofecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. Studies support the notion that the extra methylene on the isoleucine side chains in COX-1 adds enough bulk to proclude rofecoxib from binding. Rofecoxib is 100 times more selective for COX-2 than COX-1. The analgesic, antipyretic and anti-inflammatory effects of rofecoxib occurs as a result of decreased prostaglandin synthesis.  The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of rofecoxib. The latter portion of this figure depicts rofecoxib’s involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Rofecoxib preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the rare, but severe, adverse cardiovascular effects observed with rofecoxib, which has since been withdrawn from the market.


Bumetanide Action Pathway,Drug Action

Bumetanide, trade name Bumex, is a loop diuretic that increases urine production by inhibiting the reabsorption of water in the nephron. In the thick ascending limb of the loop of Henle, the sodium-potassium-chloride cotransporter (NKCC2) is competitively inhibited at the chloride binding site blocking sodium transport from the lumen to the interstitium. This results in the lumen becoming hypertonic and a decreased osmotic gradient thereby reducing the water reabsorption. In the nephron, the think ascending limb reabsorbs 25% of sodium and is a good target for diuretics.


Pravastatin Action Pathway,Drug Action

Pravastatin inhibits cholesterol synthesis via the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol synthesis by this pathway. Pravastatin bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonsotrated that statins bind to HMG-CoA reductase at the same site as the reduced reaction intermediate and are held in place by similar chemical interactions. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels. Pravstatin was derived from the microbial transformation of mevastatin, which is a natural compound produced by Penicillium citinium and the first statin ever studied. Unlike lovastatin and simvastatin, pravastatin is relatively hydrophilic and does not require hydrolysis for activation. Increased hydrophilicity accounts for its decreased penetration of lipophilic peripheral cells, increased selectivity for hepatic tissues and decreased side effects relative to simvastatin and lovastatin.


Bendroflumethiazide Action Pathway,Drug Action

Bendroflumethiazide (also known as  bendrofluazide (BAN) or Aprinox) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.


Quinethazone Action Pathway,Drug Action

Quinethazone, also known under the brand-name Hydromox, is a pharmacologically-active small molecule that belongs to a class of drugs called thiazides. Thiazides and thiazide-like drugs are diuretics commonly employed to control hypertension. The short term mechanism of action is relatively well-understood: thiazides inhibit sodium-chloride co-transport into the renal distal convoluted tubule of the nephron and therefore increase fluid loss which decreases extracellular fluid (ECF), plasma volume, and ultimately blood pressure. In the case of quinethazone, it inhibits the sodium-chloride symporter, solute carrier family 12 member 3. Thiazides also inhibit sodium ion transport. However, the long-term mechanism of action isn’t as well-characterized and it is thought that other processes beyond regulating plasma and ECF volumes are involved as these two volumes return to baseline within 4-6 weeks of first use of thiazides.


Rosuvastatin Action Pathway,Drug Action

Rosuvastatin inhibits cholesterol synthesis via the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol synthesis by this pathway. The active form of statins bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonstrated that statins bind to HMG-CoA reductase at the same site as the reduced intermediate and are held in place by similar chemical interactions. Unlike Lovastatin and simvastatin, which undergo in vivo hydrolysis to their active form rosuvastatin is synthetically produced in active form. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.


Diclofenac Action Pathway,Drug Action

Diclofenac (also named Voltaren) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat prostaglandin G/H synthase related fever, swelling, pain and inflammation. Diclofenac can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis is caused by presence of diclofenac.


Sulindac Action Pathway,Drug Action

Sulindac is a non-steroidal anti-inflammatory drug (NSAID). Like most NSAIDs, sulindac is a non-selective prostaglandin G/H synthase (a.k.a. cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). COX catalyzes the conversion of arachidonic acid to prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the precursor of a number of prostaglandins involved in fever, pain, swelling and inflammation. The analgesic, antipyretic and anti-inflammatory effects of sulindac occurs as a result of decreased prostaglandin synthesis.


Alendronate Action Pathway,Drug Action

Alendronate (also known as alendronic acid) is a type of bisphosphonate medication with nitrogen that can inhibit FPP synthase, which can block the pathway that produce geranyl-PP and farnesyl pyrophosphate. Geranyl-PP and farnesyl pyrophosphate are the compounds that are required for small GTPase signalling proteins undergo post-translational farnesylation and geranylgeranylation. Therefore, lack the formation of geranyl-PP and farnesyl pyrophosphate can prevent osteoclast activity, which lead to prevention of reduced bone resorption and turnover.


Celecoxib Action Pathway,Drug Action

Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, celecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGE2) and PGE2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precusor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Celecoxib antagonizes COX-2 by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors, such as rofecoxib and valdecoxib, celecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. Studies support the notion that the extra methylene on the isoleucine side chains in COX-1 adds enough bulk to proclude celecoxib from binding. Celecoxib is approximately ten times more selective for COX-2 than COX-1. Celecoxib is used mainly to treat rheumatoid arthritis and osteoarthritis which require something more potent than aspirin. The analgesic, antipyretic and anti-inflammatory effects of celecoxib occur as a result of decreased prostaglandin synthesis.  The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of celecoxib. The latter portion of this figure depicts celecoxib’s potential involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, which are anuclear cells derived from fragmentation of megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to the procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Celecoxib preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market.


Ethacrynic Acid Action Pathway,Drug Action

Etacrynic acid (also known as ethacrynic acid and Edecrin) is a loop diuretic that can inhibit water reabsorption by binding and inhibiting solute carrier family 12 member 1 (also known as sodium-potassium-chloride cotransporter) in the loop of Henle. Binding of the transporter can prevent import of sodium from lumen from loop of Henle to basolateral interstitium, which lead to more hypertonic environment in lumen than interstitium, and result in prevention of water reabsorption due to diminished osmotic gradient in nephron.


Ketorolac Action Pathway,Drug Action

Ketorolac (also named Toradol) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to relieve pain (analgesic), reduce fever (antipyretic) and swelling. Ketorolac can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Since prostaglandin is the messenger molecules in the process of inflammation; hence, inhibition of prostaglandin synthesis can reduce the pain, fever and inflammation.


Lovastatin Action Pathway,Drug Action

Lovastatin (also known as Mevacor or Mevinolin) is a statin drug (hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) that can be used for lowering cholesterol, treating hypercholesterolemia and preventing myocardial infarction and stroke. Lovastatin is produced by fermentation of Aspergillus terreus. HMG-CoA catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis. Lovastatin, like simvastin, is a prodrug. These prodrugs are converted to their active form by in vivo hydrolysis of the lactone ring. The hydrolyzed lactone ring resembles the tetrahedral reaction intermediate produced by HMG-CoA reductase and the bicyclic portions of these compounds bind to the coenzyme A site of the enzyme. The active drug concentrates in the liver during first-pass circulation. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.


Hydrochlorothiazide Action Pathway,Drug Action

Hydroflumethiazide (also known as Esidrix or Oretic) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.


Suprofen Action Pathway,Drug Action

Suprofen (also named Profenal and Maldocil) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to relieve pain (analgesic) and reduce fever (antipyretic). Suprofen is also a type of ophthalmic anti-inflammatory medicines which may be used to help prevent eye constrict for pupil during surgery. Suprofen can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Since prostaglandin is the messenger molecules in the process of inflammation; hence, inhibition of prostaglandin synthesis can reduce the pain and inflammation (e.g. in the eyes).


Bromfenac Action Pathway,Drug Action

Bromfenac (also named Prolensa, Bromday or Xibrom) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to reduce ocular inflammation and pain after cataract surgery. Bromfenac is also a type of ophthalmic anti-inflammatory medicines. Bromfenac can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of bromfenac.


Cyclothiazide Action Pathway,Drug Action

Cyclothiazide (also known as Anhydron or Acquirel) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.


Indomethacin Action Pathway,Drug Action

Indomethacin (also named Amuno or Indocid) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used to treat prostaglandin G/H synthase related fever, swelling, pain and inflammation.  Indomethacin can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis is caused by presence of indomethacin.


Metolazone Action Pathway,Drug Action

Metolazone (also known as Zytanix, Zaroxolyn or Mykrox) is an organic compound that used for diuretic. It can inhibit the solute carrier family 12 member 3 (also known as sodium-chloride symporter) in the nephron to prevent water reabsorption. Solute carrier family 12 member 3 is also used for sodium reabsorption that count for 5% of total amount. Solute carrier family 12 member 3 transports chloride and sodium from lumen to epithelial cell, and sodium/potassium ATPases facilitate the export of sodium to basolateral interstitium to provide sodium gradient that will increase the osmolarity in interstitium, which lead to establishment of osmotic gradient for water reabsorption.