Bile Acid Indirect Signalling Pathway,Signaling

Bile acids are taken up by enterocytes, epithelial cells of the small intestine, where they can activate the nuclear receptor farnesoid X receptor (FXR). This causes the production of fibroblast growth factor 19 (FGF19) which is then transported out of the enterocyte to the portal vein. While most FGF19 goes to the liver, some FGF19 instead enters systemic circulation where it can cross the blood brain barrier and interact with its receptors in the brain. Beta-klotho is a transmembrane protein that promotes the interaction of FGF19 and the receptor to form a stable complex. FGF receptor signaling likely plays a role in energy and glucose metabolism.


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Bile Acid Direct Signalling Pathway (2) ,Signaling

In the intestine, L-cells (enteroendocrine cells) can produce glucagon-like peptide 1 (GLP-1) after bile acid activates G-protein coupled bile acid receptor 1 on L-cells. Only small portion of GLP-1 can enter the systemic cirulation, and most of GLP-1 are degraded by dipeptidyl peptidase-4. Therefore, only small portion of GLP-1 can eventually across blood-brain barrier to interact with GLP-1 receptors


CD40L Signalling Pathway,Protein

CD40 is a part of the tumor necrosis factor (TNF) receptor superfamily. When bound to it’s main ligand CD40L, also known as CD154, CD40-CD40L interaction initializes the activation and proliferation of B lymphocytes or results in carcinoma cells apoptosis.CD40 can be expressed on many different cell surfaces such as endothelial cells, fibroblasts, hematopoietic progenitors, platelets, and basal epithelial cells. When combined with the variety of environments CD40 presenting cells can be in, the differing effects resulting from CD40 signalling is vast. However, one characteristic all CD40 mediated signalling has in common is that instead of using kinase to mediate signal transduction, signalling is performed through downstream adapter molecules. Some pathways activated by CD40-CD40L signalling include the activation of nuclear factor-κB, p38 mitogen activated protein kinase, c-Jun-NH2-kinase, signal transducers and activators of transcription, and phosphoinositide 3-kinase pathways. All of which ultimately help regulate alterations in gene expression.


G-Protein Signaling Through Tubby Proteins,Protein

Tubby protein is a part of a family of proteins called Tubby Like Proteins (TULP) characterized by 260 amino acids that form a helix-filled barrel structure at the carboxylic acid terminal (Tubby domain). Using its Tubby domain to bind phosphatidylinositol 4,5-bisphosphate (PIP2), Tubby proteins are able to localize on the plasma membrane. Through the receptor mediated activation of G-proteins, the enzyme phospholipase C–beta (PLC-beta) hydrolyses PIP2 releasing tubby from the plasma membrane. This triggers protein translocation of tubby to the nucleus allowing tubby to act as a transcription regulator.


g-Secretase Mediated ErbB4 Signalling Pathway,Protein

The HER4/erbB4-encoded protein, is a transmembrane receptor that contains a cytoplasmic tyrosine kinase domain. This domain exhibits almost 80 percent homologness with the corresponding domain of EGFR (the epidermal growth factor receptor). It was discovered in the 1990s by Plowman et al, that heregulin was responsible for inducing tyrosine phosphorylation of HER4/erbB4. ErbB4 (HER4) receptor is classified as type I GFRs. Where the tyrosine kinase growth factor receptors (GFRs) have been sub-classified into 9 different families based on the structure of their extracellular ligand binding and intracellular kinase domains and the manner in which such protein induce the ligands. Experiments revealed that erbB4 has is readily findable in heart, spleen, breast, muscle, pituitary, kidney, parathyroid, brain, and testis.


Ion Channel and Phorbal Esters Signaling Pathway,Protein

Molecules transmitting signals into cells often act through receptors in the plasma membrane that stimulate production of second messengers. When activated by a plasma membrane receptor, the enzyme phospholipase C (PLCg) hydrolyzes the membrane lipid phosphatidylinositol (PIP2) into the second messengers diacylglycerol (DAG) and IP3. IP3 releases calcium from intracellular stores into the cytoplasm where calcium alters many cellular activities, including activating protein kinase C. DAG also activates protein kinase C. Biologists often study signaling by artificially manipulating pathways using molecules like ionomycin and phorbol esters as research tools. Ionomycin is a molecule that carries calcium through the plasma membrane to increase the calcium concentration in the cytoplasm and activate protein kinase C without activating phospholipase C. Phorbol esters are molecules that mimic the action of DAG in the activation of protein kinase C, and were originally identified as tumor-promoting agents. The combination of ionomycin and phorbol esters is often used experimentally to study the effect of calcium and DAG signaling in cellular responses like T cell activation.


Circadian Rhythms,Protein

The nuclear entry of clock gene products is required to establish the negative feed back loop- a key step in proper circadian rhythm. Heterodimerization of clock proteins PER and CRY is required for translocation to the nucleus. Nuclear entry of PER can be regulated by mammalian casein kinase I (CK1). Once in the nucleus, PER and CRY proteins appear to differentially inhibit the transactivation by CLOCK/BMAL1. Proteins like REV-ERBa and DEC also regulate the transcriptional activation by CLOCK/BMAL1. In addition, CRY, PER, and BMAL1-CLOCK play bidirectional roles in transcription resulting in interactivating feedback loops. The expression of BMAL1 and CLOCK can be upregulated by CRY and PER. Such loops are believed to be important in the stability and persistence of circadian rhythm.


Hop Pathway in Cardiac Development,Physiological

Homeodomain transcription factors comprise a large family of DNA binding factors that regulate transcription and development. Many homeodomain genes arranged in genomic clusters determine anterior-posterior patterning, while others determine the fate of cells in specific tissues. The proliferation of cardiac myocytes and their differentiation early in development are both dependent on the coordinate expression and action of serum response factor (SRF), GATA4 and the homeodomain factor Nkx2-5. All three of these factors are expressed in developing cardiomyocytes and induce expression of cardiac genes. Disruption of the Nkx2-5 gene in mice leads to embryonic lethality and defective cardiac development. SRF also plays a duel role in cardiac development, influencing both cardiomyocyte proliferation and differentiation depending on the stage and other signals that are present.In addition, the Hop (Homeodomain Only Protein) gene encodes a factor expressed early in cardiac development that is involved in cardiac differentiation. Hop inactivation in vertebrates leads to severe defects in cardiac development, acting downstream of Nkx2-5. Cardiac cells from mice lacking the Hop gene fail to exit the cell cycle in the normal manner, continuing to proliferate past the normal developmental stage. Many of the genes disregulated in the absence of Hop are involved in the cell cycle and are also targets of SRF. Although Hop is a homeodomain protein, it lacks a DNA-binding domain indicating that it must not regulate gene expression directly. Hop appears to regulate the expression of cardiac genes by binding to SRF and blocking DNA binding of SRF. The sequestration of SRF by Hop blocks the activation of cardiac genes, preventing normal cardiac development. The influence of Hop on the opposing processes of cardiomyocyte differentation and proliferation reflect the interaction of Hop with SRF and the duel role SRF plays. In early cardiac development, Hop opposes differentiation induction by SRF, while at later stages Hop opposes the proliferation induced by SRF.


LPS and Citrate Signaling and Inflammation,Protein

Citrate is an important substrate in cellular energy metabolism, which is produced by mitochondria and used in Krebs cycle or released into cytoplasm through a specific mitochondrial carrier, CIC. In the cytosol, citrate and its derivatives, acetyl-CoA and oxaloacetate, are used in normal and pathological processes. Apart from the classical role as metabolic regulator, citrate is also involved in inflammation, cancer, insulin secretion, histone acetylation, neurological disorders and non-alcoholic fatty lever disease.


Protein Synthesis: Alanine,Protein

Protein synthesis is an essential life process that builds the important large amino acid macromolecules that function as enzymes, antibodies, and cellular structural components. Although synthesis begins with the transcription of DNA into RNA, this pathway depicts the reactions that occur during translation. Transcribed messenger RNA (mRNA), which contains the genetic code to direct protein synthesis, is transported out of the nucleus and becomes bound to ribosomes in the cytoplasm or endoplasmic reticulum. The amino acids required to assemble polypeptide chains are delivered to the ribosomes using transfer RNA (tRNA). Each tRNA molecule has both a binding site for a specific amino acid and a three-nucleotide sequence called the anticodon that forms three complementary base pairs with an mRNA codon. Charging or loading the appropriate amino acid onto its tRNA is carried out by an aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase. This enzyme catalyzes the esterification of an amino acid to one of all its compatible tRNAs to form an aminoacyl-tRNA. Each of the twenty amino acids has a corresponding aa-tRNA made by a specific aminoacyl-tRNA synthetase. Ribosomes match the anticodons of the charged tRNA molecules with successive codons of the mRNA. After a match is found, the ribosome transfers the amino acid from the matching tRNA onto the growing peptide chain via a reaction termed peptide condensation, and the tRNAs, no longer carrying amino acids, are released.


Protein Synthesis: Aspartic Acid,Protein


Protein Synthesis: Glutamic Acid,Protein


Kidney Function- Proximal Convoluted Tubule,Physiological

The proximal convoluted tubule is part of the nephron between the Bowman's capsule and the loop of Henle. The proximal convoluted tubule functions to reabsorb sodium, water, and other ions. Sodium and bicarbonate (hydrogen carbonate) are transported by a co-transporter that is responsible for the majority of sodium reabsorption. The bicarbonate, along with hydrogen, are exchanged across the basal and apical membranes, respectively, to effectively regulate the pH of the filtrate.  In addition, chloride ions are not normally reabsorbed in large amounts at the proximal tubule compared to other parts of the nephron.  However, the reabsorption of chloride, as well as potassium, increases as the amount of water reabsorption increases due to solvent drag (also known as bulk transport).  This occurrence explains solute movement secondary to water flow.  All the cation and anion transport creates a gradient favourable for ion and water reabsorption, leading to an increase in blood pressure.


Kidney Function - Descending Limb of the Loop of Henle,Physiological

The loop of Henle of the nephron can be separated into an ascending limb and the descending limb.  The ascending limb is highly impermeable to water, but permeable to solutes.  Conversely, the descending limb is highly impermeable to solutes such as sodium, but permeable to water.  As solutes are being actively transported out of the ascending limb, the solutes cause in increase in osmotic pressure.  This, combined with the ability for water to move freely out of the descending limb, leads to a water reabsorption into the adjacent capillary network and a high concentration of sodium in the filtrate at the descending Limb.  Water moves from the descending loop to the capillary network through aquaporin channels in the cell membrane.


Kidney Function - Ascending Limb of The Loop of Henle,Physiological

The loop of Henle of the nephron can be separated into an ascending limb and the descending limb.  The descending limb is highly impermeable to solutes such as sodium, but permeable to water.  Conversely, the ascending limb is highly impermeable to water, but permeable to solutes. Chloride, potassium, and sodium are co-transported across the apical membrane (closest to the lumen) via transporters from the filtrate. The transporter requires all three ions present to be effective and to maintain electroneutrality. In addition, the three ions are transported across the basolateral membrane (closest to the renal interstitium) via other means such as the sodium potassium ATPase transports and the chloride channels in the membrane. As these solutes are being actively transported out of the ascending limb and into the renal interstitium/capillary network without water following (due to the lack of water permeability), the filtrate becomes more diluted. Furthermore, these ions simultaneously causes an increase in osmotic pressure that contributes to water reabsorption in the descending limb.  This effect can be magnified with the help of vasopressin, which is a hormone that is typically involved with water reabsorption.  However, when it acts on the ascending limb, it aids in increasing sodium reabsorption which will increase water reabsorption in the latter parts of the nephron (the distal tubule and collecting duct).


Kidney Function - Collecting Duct,Physiological

The collecting duct of the nephron is the last segment of the functioning nephron and is connected to minor calyces and the ensuing renal pelvis of the kidney where urine continues before it is stored in the bladder.  The collecting duct is mainly responsible for the excretion and reabsorption of water and ions. It is composed of two important cell types: intercalated cells that are responsible for maintaining acid-base homeostasis, and principal cells that help maintain the body's water and salt balance.  When renin is released from the kidneys, it causes the activation of angiotensin I in the blood circulation which is cleaved to become angiotensin II. Angiotensin II stimulates the release of aldosterone from the adrenal cortex and release of vasopressin from the posterior pituitary gland.  When in the circulation, vasopressin eventually binds to receptors on epithelial cells in the collecting ducts.  This causes vesicles that contain aquaporins to fuse with the plasma membrane.  Aquaporins are proteins that act as water channels once they have bound to the plasma membrane.  As a result, the permeability of the collecting duct changes to allow for water reabsorption back into the blood circulation.  In addition, sodium and potassium are also reabsorbed back into the systemic circulation at the collecting duct via potassium and sodium channels. However, aldosterone is a major regulator of the reabsorption of these ions as well, as it changes the permeability of the collective duct to these ions.  As a result, a high concentration of sodium and potassium in the blood vessels occurs. Some urea and other ions may be reabsorbed as well. The reabsorption of ions and water increases blood fluid volume and blood pressure.


Kidney Function - Distal Convoluted Tubule,Physiological

The distal convoluted tubule of the nephron is the part of the kidney between the loop of henle and the collecting duct. When renin is released from the kidneys, it causes the activation of angiotensin I in the blood circulation which is cleaved to become angiotensin II. Angiotensin II stimulates the release of aldosterone from the adrenal cortex and release of vasopressin from the posterior pituitary gland.  When in the circulation, vasopressin eventually binds to receptors on epithelial cells in the distal convoluted tubule.  This causes vesicles that contain aquaporins to fuse with the plasma membrane.  Aquaporins are proteins that act as water channels once they have bound to the plasma membrane.  As a result, the permeability of the distal convoluted tubule changes to allow for water reabsorption back into the blood circulation. In addition, sodium, chlorine, and calcium are also reabsorbed back into the systemic circulation via their respective channels and exchangers. However, aldosterone is a major regulator of the reabsorption of these ions as well, as it changes the permeability of the distal convoluted tubule to these ions.  As a result, a high concentration of sodium, chlorine, and calcium in the blood vessels occurs. The reabsorption of ions and water increases blood fluid volume and blood pressure.


Pancreas Function - Beta cell,Physiological

Beta cells are found in pancreatic islet cells and their main function is to release insulin.  Insulin counteracts glucagon and functions to maintain glucose homeostasis when glucose levels are high.  Insulin is contained in granules in the cell as a reserve ready to be released, which is dependent on extracellular glucose levels, and intracellular calcium levels and/or various proteins that activate the vesicle-associated membrane protein on the insulin granules' membranes.  In the process of insulin secretion, glucose must first undergo glycolysis to increase ATP in the cell.  The inside of the beta cell then becomes electrically positive due to the closure of potassium channels that were inhibited by ATP.  From this closure, the potassium is no longer being shuttled out of the cell, thus depolarizing the cell due to the extra intracellular potassium.  The resulting action potential from the increased membrane potential causes the voltage gate calcium channels to open, creating an influx of calcium into the cell.  This triggers the vesicle-associated membrane protein on the outside of the insulin granule to tether, dock, and fuse with the beta cell membrane.  Insulin is then exocytosed from the cell.  However, the vesicle-associated membrane protein can be activated by other means in addition to calcium.  Acetylcholine can bind to muscarinic acetylcholine receptors on the cell membrane and trigger a G protein cascade.  This eventually leads to the activation of inositol trisphosphate to cause calcium release from the rough endoplasmic reticulum so that it can activate the calcium/calmodulin-dependent protein kinase to trigger the vesicle-associated membrane protein.  The G protein cascade can also lead to the activation of diacylglycerol and subsequently protein kinase C to lead to the same outcome.  Glucagon-like peptide can also trigger a similar G protein cascade when it binds to glucagon-like peptide receptors on the cell membrane of the beta cell.  This process involves cAMP and a few other proteins in order to lead to the same eventual outcome of triggering the vesicle-associated membrane protein and the exocytosis of insulin from the beta cell.


Pancreas Function - Alpha cell,Physiological

Alpha cells are a type of islet cell found in the pancreas that release glucagon. Glucagon counteracts insulin and functions to maintain glucose homeostasis when detected glucose levels are low. Glucagon is contained in granules in the cell as a reserve ready to be released. Extracellular glucose levels and ion channels regulate the secretion of glucagon.  Glucose undergoes glycolysis to increase ATP in the cell. The moderate activity of potassium ATP channels causes the membrane potential to be around -70mV. The alpha cell then becomes electrically active due to the closure of potassium channels. The cell membrane becomes depolarized due to voltage dependent sodium, potassium and calcium channels. This causes an increase in action potentials and opens voltage gate calcium channels causing an increase of calcium into the cell. This triggers the exocytosis of glucagon from the cell.  Conversely, an increase in extracellular glucose leads to an increase in ATP production and inhibition of potassium ATP channels. The membrane depolarizes to a membrane potential that inactivates voltage dependent calcium channels. This results in decreased intracellular calcium and inhibits exocytosis of glucagon.


Mevalonate Pathway,Metabolic

The Mevalonate Pathway is a necessary pathway that occurs in archaea, eukaryotes and select bacteria. It has mainly been studied with regard to cholesterol biosynthesis and how it relates to cardiovascular disease in humans, but has recently garnered attention for its many other essential roles within human pathology.  The pathway begins in the cytoplasm with acetyl-CoA and acetoacetyl-CoA, which interact with acetyl-CoA acetyltransferase, coenzyme A and water to synthesize hydroxymethylglutaryl-CoA synthase. In turn, this synthase teams up with coenzyme A and a hydrogen ion in the endoplasmic reticulum to create 3-hydroxy-3-methylglutaryl-CoA. 3-Hydroxy-3-methylglutaryl-CoA then pairs with 2NADPH, 2 hydrogen ions and is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase to produce (R)-mevalonate, also producing byproducts CoA and NADP. Exiting the endoplasmic reticulum, and entering the peroxisome, (R)-mevalonate uses the help of ATP and mevalonate kinase to create mevalonic acid (5P). This piece is especially important to the human species as decreased activity of the enzyme mevalonate kinase has been found to be a direct link to two auto-inflammatory disorders: MVA and HIDS. Using phosphomevalonate kinase and ATP, the pathway re-enters the cytoplasm and mevalonic acid (5P) converts to (R)-mevalonic acid-5-pyrophosphate and ADP. (R)-mevalonic acid-5-pyrophosphate, ATP and diphosphomevalonate decarboxylase work together to create phosphate, carbon dioxide, ADP and isopentenyl pyrophosphate. Re-entering the peroxisome, isopentenyl diphosphate delta isomerase 1 is waiting to propel isopentenyl pyrophosphate into dimethylallylpyrophosphate. This pushes the pathway back into the cytoplasm, where another isopentenyl pyrophosphate molecule and the enzyme farnesyl pyrophosphate synthase create pyrophosphate and geranyl-PP. Yet another isopentenyl pyrophosphate molecules works with farnesyl pyrophosphate synthase to produce pyrophosphate and farnesyl pyrophosphate. Now in the endoplasmic reticulum membrane, 2 farnesyl pyrophosphate molecules with the help of NADPH and a hydrogen ion catalyze with squalene synthase and create squalene. This is an important first step in the specific hepatic cholesterol pathway. Remaining in the endoplasmic reticulum membrane, squalene, FMNH, oxygen and squalene monooxygenase synthesize (S)-2,3-epoxysqualene. This comes along with the byproducts of flavin mononucleotide, a hydrogen ion and water. In the final reaction within this pathway,  lanesterol synthase converts (S)-2,3-epoxysqualene to lanosterin. Not pictured in this pathway, lanosterin will eventually be converted to cholesterol, an important part of many functions in the human body.


Bloch Pathway (Cholesterol Biosynthesis) ,Metabolic

The Bloch pathway, named after Konrad Bloch, is the pathway following the mevalonate pathway occurring within the cell to complete cholesterol biosynthesis. Cholesterol is a necessary metabolite that helps create many essential hormones within the human body. This pathway, combined with the mevalonate pathway is one of two ways to biosynthesize cholesterol; the Kandutsch-Russell pathway is an alternative pathway that uses different compounds than the Bloch Pathway beginning after lanosterol. The first three reactions occur in the endoplasmic reticulum. Lanosterol, a compound created through the mevalonate pathway, binds with the enzyme lanosterol 14-alpha demethylase to become 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol. Moving to the next reaction, 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol utilizes the enzyme lanosterol 14-alpha demethylase to create 4,4-dimethyl-14α-formyl-5α-cholesta-8,24-dien-3β-ol. Lanosterol 14-alpha demethylase is used one last time in this pathway, converting 4,4-dimethyl-14α-formyl-5α-cholesta-8,24-dien-3β-ol into 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol. Entering the inner nuclear membrane, 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol is catalyzed by a lamin B receptor to create 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol. Entering the endoplasmic reticulum membrane, 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol, with the help of methyl monooxygenase 1 is converted to 4a-hydroxymethyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol. The enzyme methyl monooxygenase 1 uses 4a-hydroxymethyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol to produce 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol. This reaction is repeated once more, using 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3b-ol and methyl monooxygenase 1 to create 4a-carboxy-4b-methyl-5a-cholesta-8,24-dien-3b-ol. Briefly entering the endoplasmic reticulum, 4a-carboxy-4b-methyl-5a-cholesta-8,24-dien-3b-ol then uses sterol-4-alpha-carboxylate-3-dehyrogenase to catalyze into 3-keto-4-methylzymosterol. Back in the endoplasmic reticulum membrane, where the pathway will continue on for the remaining reactions, 3-keto-4-methylzymosterol combines with 3-keto-steroid reductase to create 4a-methylzymosterol. 4a-Methylzymosterol joins the enzyme methylsterol monooxgenase 1 to result in 4a-hydroxymethyl-5a-cholesta-8,24-dien-3b-ol. 4a-Hydroxymethyl-5a-cholesta-8,24-dien-3b-ol uses methylsterol monooxygenase 1 to convert to 4a-formyl-5a-cholesta-8,24-dien-3b-ol. 4a-Formyl-5a-cholesta-8,24-dien-3b-ol proceeds to use the same enzyme used in the previous reaction: methylsterol monooxygenase 1, to catalyze into 4a-carboxy-5a-cholesta-8,24-dien-3b-ol. Sterol-4-alpha-carboxylate-3-dehydrogenase is used alongside 4a-carboxy-5a-cholesta-8,24-dien-3b-ol to produce 5a-cholesta-8,24-dien-3-one (also known as zymosterone). Zymosterone (5a-cholesta-8,24-dien-3-one) teams up with 3-keto-steroid reductase to create zymosterol. Zymosterol proceeds to use the enzyme 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase to catalyze into 5a-cholesta-7,24-dien-3b-ol. The compound 5a-cholesta-7,24-dien-3b-ol then joins lathosterol oxidase to convert to 7-dehydrodesmosterol. 7-Dehydrodesmosterol and the enzyme 7-dehydrocholesterol reductase come together to create desmosterol. This brings the pathway to the final reaction, where desmosterol combines with delta(24)-sterol reductase to finally convert to cholesterol.


Kandutsch-Russell Pathway (Cholesterol Biosynthesis),Metabolic

The Kandutsch-Russell pathway is the alternative pathway stemming from the mevalonate pathway completing cholesterol biosynthesis. The Bloch pathway and the Kandutsch-Russell pathway are both key to a functioning human body as cholesterol aids in the development of many important nutrients and hormones, such as vitamin D. Starting in the endoplasmic reticulum, lanosterol is the first compound used in this pathway, and when catalyzed by delta(24)-sterol-reductase, becomes 24,25-dihydrolanosterol. 24,25-Dihydrolanosterol is quickly converted to 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8-en-3b-ol with the help of the enzyme lanosterol 14-alpha demethylase. This same enzyme, lanosterol 14-alpha demethylase, is also responsible for the conversion of 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8-en-3b-ol into 4,4-dimethyl-14a-formyl-5a-cholest-8-en-3b-ol. Lanosterol 14alpha demethylase is used once more here, to push the pathway into the inner nuclear membrane, converting 4,4-dimethyl-14a-formyl-5a-cholest-8-en-3b-ol into 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol. Now located in the inner nuclear membrane, 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol is converted into 4,4-dimethyl-5a-cholesta-8-en-3b-ol through the help of a lamin-b receptor. Entering the endoplasmic reticulum membrane, methylsterol monooxygenase 1 is used to convert 4,4-dimethyl-5a-cholesta-8-en-3b-ol into 4a-hydroxymethyl-4b-methyl-5a-cholesta-8-en-3b-ol. 4a-Hydroxymethyl-4b-methyl-5a-cholesta-8-en-3b-ol then uses methylsterol monooxygenase 1 to become 4a-formyl-4b-methyl-5a-cholesta-8-en-3b-ol. Once again, methylsterol monooxygenase 1 is used to convert 4a-formyl-4b-methyl-5a-cholesta-8-en-3b-ol into 4a-carboxy-4b-methyl-5a-cholesta-8-en-3b-ol. Now using sterol-4-alpha-carboxylate 3-dehydrogenase, 4a-carboxy-4b-methyl-5a-cholesta-8-en-3b-ol is turned into 4a-methyl-5a-cholesta-8-en-3-one. This puts the pathway in the cell membrane, where a 3-keto-steroid reductase is used to convert 4a-methyl-5a-cholesta-8-en-3b-one into  4a-methyl-5a-cholesta-8-en-3-ol. Moving back into the endoplasmic reticulum membrane, methylsterol monooxygenase 1 converts 4a-methyl-5a-cholesta-8-en-3-ol into 4a-hydroxymethyl-5a-cholesta-8-en-3b-ol. Methylsterol monooxygenase is used twice more in this pathway, first converting 4a-hydroxymethyl-5a-cholesta-8-en-3b-ol into 4a-formyl-5a-cholesta-8-en-3b-ol, then converting 4a-formyl-5a-cholesta-8-en-3b-ol into 4a-carboxy-5a-cholesta-8-en-3b-ol. Now using sterol-4-alpha-carboxylate 3 dehydrogenase, 4a-carboxy-5a-cholesta-8-en-3b-ol becomes 5a-cholesta-8-en-3-one and brings the pathway back to the cell membrane. 5a-Cholesta-8-en-3-one teams up with a 3-keto-steroid reductase to create 5a-cholest-8-en-3b-ol. Then, stepping back into the endoplasmic reticulum membrane, 5a-cholest-8-en-3b-ol enlists the help of 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase to produce lathosterol. Lathosterol and lathosterol oxidase work together to make 7-dehydrocholesterol . Finally, 7-dehydrocholesterol partners with 7-dehydrocholesterol reductase to create cholesterol, completing the final step in cholesterol biosynthesis.


Arsenate Detoxification,Metabolic

Arsenate is a compound similar to phosphate, but containing an arsenic atom instead of the phosphorous. As such, it is treated similarly to a phosphate ion. However, if the arsenate replaces inorganic phosphates in glycolysis, it allows glycolysis to proceed, but does not generate ATP, uncoupling glycolysis. It can also bind to lipoic acid in the Krebs cycle, leading to a greater loss of ATP.Arsenate can enter into the cell via aquaporins 7 and 9, as well as facilitated glucose transporter members 1 and 4 of solute carrier family 2, and does so by diffusion.Once inside the cell, the arsenate can be converted to arsenite via the glutathione S-transferase omega-1 enzyme, or it can be converted to ribose-1-arsenate via the purine nucleoside phosphorylase. Ribose-1-arsenate then can spontaneously form arsenite through a reaction involving hydrogen and dihydrolipoate. After arsenite has been formed by either of these methods, arsenite methyltransferase catalyzes its formation into methylarsonate. From here, it forms methylarsonite via the glutathione S-transferase omega-1 enzyme again. The methylarsonite reacts with S-adenosylmethionine, catalyzed by arsenite methyltransferase, in order to become dimethylarsinate. Finally, the compound once again interacts with the glutathione S-transferase omega-1 enzyme to form dimethylarsinous acid, the final compound in this pathway.


Aldosterone from Steroidogenesis ,Physiological

Aldosterone is a hormone produced in the zona glomerulosa of the adrenal cortex.  It's function is to act on the distal convoluted tubule and the collecting duct of the nephron to make them more permeable to sodium to allow for its reuptake (in addition to allowing potassium wasting).  As a result, water follows the sodium back into the body. The water retention contributes to an increased blood volume.  Angiotensin II from the circulation binds to receptors on the zona glomerulosa cell membrane, activating the G protein and triggering a signaling cascade.  The end result is the activation of the steroidogenic acute regulatory (StAR) protein that permits cholesterol uptake into the mitochondria.  From there, cholesterol undergoes a series of reactions in both the mitochondrion and the smooth endoplasmic reticulum (steroidogenesis) where it finally becomes aldosterone.


Pancreas Function - Delta Cell,Physiological

Pancreatic delta cells produce somatostatin which functions to inhibit glucagon, insulin, and itself.  Somatostatin is stored in granules in the delta cell and is released in response to an increase in blood sugar, calcium, and blood amino acids during absorption of a meal. In the process of somatostatin secretion, glucose must first undergo glycolysis in the mitochondrion to increase ATP in the cell. The inside of the alpha cell then becomes electrically positive due to the closure of potassium channels that were inhibited by ATP.  From this closure, the potassium is no longer being shuttled out of the cell, thus depolarizing the cell due to the extra intracellular potassium.  The resulting action potential from the increased membrane potential causes the voltage gate calcium channels to open, creating an influx of calcium into the cell.  This triggers the exocytosis of somatostatin granules from the delta cell.


This pathway is part of a major route of the degradation of L-tryptophan. It begins with 2-amino-3-carboxymuconate-6-semialdehyde which is generated from L-tryptophan degradation. The 2-amino-3-carboxymuconate-6-semialdehyde first is acted upon by a decarboxylase, forming 2-aminomuconic acid semialdehyde, which is then dehydrogenated by 2-aminomuconic semialdehyde dehydrogenase to form 2-aminomuconic acid. An unknown protein forms a 2-aminomuconate deaminase which forms (3E)-2-oxohex-3-enedioate, and a second unknown protein forms a 2-aminomuconate reductase, which forms oxoadipic acid from (3E)-2-oxohex-3-enedioate. Finally, within the mitochondria, oxoadipic acid is dehydrogenated and a coenzyme A is attached by the organelle’s oxoglutarate dehydrogenase complex, forming glutaryl-CoA. Glutaryl-CoA can then be further degraded.


cyclosporine

Cyclosporine, also known as neoral or sandimmune, belongs to the class of organic compounds known as cyclosporins. These are cyclic depsipeptides containing the cyclosporin backbone. Cyclosporine is a drug which is used for treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis. . Cyclosporine exists as a solid and is considered to be practically insoluble (in water) and relatively neutral. Cyclosporine can be converted into cyclosporin a derivative..


Seproxetine

Norfluoxetine is a metabolite of fluoxetine. (S)-Norfluoxetine, also known as seproxetine, is a selective serotonin reuptake inhibitor (SSRI). It is the most important active metabolite of the widely used antidepressant fluoxetine but little is known about its pharmacological actions. Seproxetine was being investigated by Eli Lilly and Company as an antidepressant, however, a cardiac side effect was noted and development was discontinued (Wikipedia).


Choline magnesium trisalicylate

Trisalicylate-choline is only found in individuals that have used or taken this drug. It is a non-acetylated salicylate used widely as a nonsteroidal anti-inflammatory drug. Trisalicylate significantly reduces methotrexate renal clearance, displacing methotrexate from protein, increasing the fraction unbound by 28%.(PMID: 1728115, 1618240)Trisalicylate-choline inhibits prostaglandin synthesis; acts on the hypothalamus heat-regulating center to reduce fever; blocks the generation of pain impulses

Tricosal
Choline magnesium trisalicylic acid


PC(18:0/18:0) is a phosphatidylchloline (PC). It is a glycerophospholipid in which a phosphorylcholine moiety occupies a glycerol substitution site. As is the case with diacylglycerols, phosphatidylcholines can have many different combinations of fatty acids of varying lengths and saturation attached to the C-1 and C-2 positions. PC(18:0/18:0), in particular, consists of two octadecanoyl chains at positions C-1 and C-2. In E. coli, PCs can be found in the integral component of the cell outer membrane. They are hydrolyzed by Phospholipases to a 2-acylglycerophosphocholine and a carboxylate.


Ibandronate

Ibandronate is a nitrogen-containing bisphosphonate in the same class as alendronate and risedronate. Ibandronate inhibits osteoclast-mediated bone resorption. All of the bisphosphonates prevent the breakdown of bone by bone cells called osteoclasts. In persons who are at high risk for osteoporosis, bisphosphonates not only result in increased amounts of bone and bone strength, they also reduce the risk of hip fractures and other bone fractures.

Ibandronate sodium monohydrate
Ibandronic acid
R484
Bondronat
Ibandronate


Ardeparin

Enoxaparin is a low molecular weight heparin. It is used to prevent and treat deep vein thrombosis or pulmonary embolism, and is given as a subcutaneous injection. Enoxaparin binds to and accelerates the activity of antithrombin III. By activating antithrombin III, enoxaparin preferentially potentiates the inhibition of coagulation factors Xa and IIa. Factor Xa catalyzes the conversion of prothrombin to thrombin, so enoxaparin's inhibition of this process results in decreased thrombin and ultimately the prevention of fibrin clot formation. Low molecular weight heparins are less effective at inactivating factor IIa due to their shorter length compared to unfractionated heparin.


A4Z6T9_HUMAN arylamine N-acetyltransferase (trembl)


A8E194_HUMAN Bcr-abl1 fusion protein (Fragment) (trembl)


A9Z1X1_HUMAN 6-phosphogluconate dehydrogenase, decarboxylating (trembl)


B7ZKV8_HUMAN Sodium/potassium-transporting ATPase subunit beta (trembl)


H0YLL5_HUMAN Isocitrate dehydrogenase (NADP(+)) 2 (trembl)


GCYB2_HUMAN Guanylate cyclase soluble subunit beta-2 (sprot)


TRAC_HUMAN T cell receptor alpha chain constant (sprot)


TRBC1_HUMAN T cell receptor beta constant 1 (sprot)


IGHE_HUMAN Immunoglobulin heavy constant epsilon (sprot)


RL19_ECOLI Large ribosomal subunit protein bL19 (sprot)


ALAA_ECOLI Glutamate-pyruvate aminotransferase AlaA (sprot)


CBS_HUMAN Cystathionine beta-synthase (sprot)


ALAC_ECOLI Glutamate-pyruvate aminotransferase AlaC (sprot)


Q6LAP8_HUMAN Tricarboxylate transport protein, mitochondrial (Fragment) (trembl)


LRRC7_HUMAN Leucine-rich repeat-containing protein 7 (sprot)


Q9H302_HUMAN NADP+-specific isocitrate dehydrogenase (Fragment) (trembl)


Q9H9C5_HUMAN Ubiquitin carboxyl-terminal hydrolase (trembl)


Q9WJQ2_HV1 Reverse transcriptase protein (Fragment) (trembl)