Browsing Pathways

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.

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.

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.

Vitamin K describes a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and synthetically in three others): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofacter in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NAD(P)H dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To complete the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include a number of important coagulation factors, such as prothrombin. Thus, warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase.

In the majority of organisms, fatty acid degradation occurs mostly through the beta-oxidation cycle. In plants, this cycle only happens in the peroxisome, while in mammals this cycle happens in both the peroxisomes and mitochondria. Unfortunately, traditional fatty acid oxidation does not work for branched-chain fatty acids, or fatty acids that do not have an even number of carbons, like the fatty acid phytanic acid, found in animal milk. This acid can not be oxidized through beta-oxidation, as problems arise when water is added at the branched beta-carbon. To be able to oxidize this fatty acid, the carbon is oxidized by oxygen, which removes the initial carboxyl group, which shortens the chain. Now lacking a methyl group, this chain can be beta-oxidized. Now moving to the mitochondria, there are four reactions that occur, and are repeated for each molecule of the fatty acid. Each time the cycle of these reactions is completed, the chain is relieved of two carbons, which are oxidized and are taken away by NADH and FADH2, energy carriers that collect the carbons energy. After beta-oxidation in the cycle of reactions, an acetyl-CoA unit is released and is recycled into the cycle of reactions in the mitochondria, until the chain is fully broken down into acetyl-CoA, and can enter the TCA cycle. Once in the TCA cycle, it is converted to NADH and FADH2, which in turn help move along mitochondrial ATP production. Acetyl-CoA also helps produce ketone bodies that are further converted to energy in the heart and the brain.

The biosynthesis of fatty acids primarily occurs in liver and lactating mammary glands. The entire synthesis process which produces palmitic acid occurs on a multifunctional dimeric protein Fatty Acid Synthase (FA) in the cytosol. The production of palmitic acid can be summarized as the successive addition of two carbons to an initial acetyl moiety primer. After 7 cycles palimitic acid is released. The synthesis starts with the sequential transfer of a primer substrate, acetyl-CoA, to the nucleophilic serine residue of the acyltransferase domain of FA. The acetyl moiety is then transferred to the Acyl Carrier Protein (ACP) domain of FA, then finally to the active site of the beta-ketoacyl synthase domain. A chain extender substrate, molonyl-CoA, is transferred to the nucleophilic serine residue of the acyltransferase domain and subsequently to the ACP domain. The acetyl moiety is extend by a condensation reaction, catalysed by the beta-ketoacyl synthase domain, that produces a new Carbon-Carbon bound, this reaction is coupled to a decarboxylation resulting in the production of carbon dioxide. Subsequently beta-ketoacyl condensation product is reduced to a saturated acyl moiety through the step wise action on the beta-ketoacyl reductase, beta-hydroxyacyl dehydrase and enoyl reductase domains respectively. This saturated acyl moiety is then transfer back to the active site of the beta-ketoacyl synthase domain, another molonyl-CoA is loaded and the process repeats. The addition of molonyl moieties occurs 7 times after which the final product is released by that action of thioesterase domain. The final product is 16 carbon long palmitic acid.

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.

The malate-aspartate shuttle system, also called the malate shuttle, is an essential system used by mitochondria, that allows electrons to move across the impermeable membrane between the cytosol and the mitochondrial matrix. The electrons are created during glycolysis, and are needed for oxidative phosphorylation. The malate-aspartate shuttle is needed as the inner membrane is not permeable to NADH or NAD+, but is permeable to the ions that attach to malate. When the malate gets inside the membrane,the energy inside of malate is taken out by creating NADH from NAD+, which regenerates oxaloacetate. NADH can then transfer electrons to the electron transport chain.

Phosphatidylcholines (PC) are a class of phospholipids that incorporate a phosphocholine headgroup into a diacylglycerol backbone. They are the most abundant phospholipid in eukaryotic cell membranes and has both structural and signalling roles. In eukaryotes, there exist two phosphatidylcholine biosynthesis pathways: the Kennedy pathway and the methylation pathway. The Kennedy pathway begins with the direct phosphorylation of free choline into phosphocholine followed by conversion into CDP-choline and subsequently phosphatidylcholine. It is the major synthesis route in animals. The methylation pathway involves the 3 successive methylations of phosphatidylethanolamine to form phosphatidylcholine. The first reaction of the Kennedy pathway involves the cytosol-localized enzyme choline/ethanolamine kinase catalyzing the conversion of choline into phosphocholine. Second, choline-phosphate cytidylyltransferase, localized to the endoplasmic reticulum membrane, catalyzes the conversion of phosphocholine to CDP-choline. Last, choline/ethanolaminephosphotransferase catalyzes phosphatidylcholine biosynthesis from CDP-choline. It requires either magnesium or manganese ions as cofactors. A parallel Kennedy pathway forms phosphatidylethanolamine from ethanolamine - the only difference being a different enzyme, ethanolamine-phosphate cytidylyltransferase, catalyzing the second step. Phosphatidylethanolamine is also synthesized from phosphatidylserine in the mitochondrial membrane by phosphatidylserine decarboxylase. Phosphatidylethanolamine funnels into the methylation pathway in which phosphatidylethanolamine N-methyltransferase (PEMT) then catalyzes three sequential N-methylation steps to convert phosphatidylethanolamine to phosphatidylcholine. PEMT uses S-adenosyl-L-methionine as a methyl donor.

Androstenedione is an endogenous weak androgen steroid hormone that is a precursor of testosterone and other androgens, as well as of estrogens like estrone . Its metabolism occurs primarily in the endoplasmic reticulum (membrane-associated enzymes are coloured dark green in the image). Conversion of androstenedione to testosterone requires the enzyme testosterone 17-beta-dehydrogenase 3. Conversion of androstenedione to estrone involves three successive reactions catalyzed by the enzyme aromatase (cytochrome P450 19A1). Androstenedione can also be converted into etiocholanolone glucuronide, androsterone glucuronide, and adrenosterone. The three-reaction subpathway to synthesize etiocholanolone glucuronide begins with the enzyme 3-oxo-5-beta-steroid 4-dehydrogenase catalyzing the conversion of androstenedione to etiocholanedione. This is followed by the conversion of etiocholanedione to etiocholanolone which is catalyzed by aldo-keto reductase family 1 member C4. Lastly, the large membrane-associated multimer UDP-glucuronosyltransferase 1-1 catalyzes the conversion of etiocholanolone to etiocholanolone glucuronide. The three-reaction subpathway to synthesize androsterone glucuronide begins with the conversion of androstenedione to androstanedione via 3-oxo-5-alpha-steroid 4-dehydrogenase 1. Anstrostanedione is then converted into androsterone via aldo-keto reductase family 1 member C4. The last reaction to form androsterone glucuronide is catalyzed by the large multimer UDP-glucuronosyltransferase 1-1. The two-reaction subpathway to synthesize adrenosterone begins in the mitochondrial inner membrane where androstenedione is first converted into 11beta-hydroxyandrost-4-ene-3,17-dione by the enzyme cytochrome P450 11B1. Following transport to the endoplasmic reticulum, 11beta-hydroxyandrost-4-ene-3,17-dione is converted into adrenosterone via corticosteroid 11-beta-dehydrogenase isozyme 1.