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HMG-CoA
β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate pathway, mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery. HMG-CoA is a metabolic intermediate in the metabolism of the branched-chain amino acids, which include leucine, isoleucine, and valine. Its immediate precursors are β-methylglutaconyl-CoA (MG-CoA) and β-hydroxy β-methylbutyryl-CoA (HMB-CoA). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Biosynthesis Mevalonate pathway Mevalonate synthesis begins with the beta-ketothiolase-catalyzed Claisen condensation of two molecules of acetyl-CoA to produce Acetoacetyl-CoA, acetoacetyl CoA. The following reaction involves the joining of acetyl-C ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
HMG-CoA Reductase
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-limiting enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia. HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum, and was long regarded as having seven transmembrane domains, with the active site located in a long carboxyl terminal domain in the cytosol. More recent evidence shows it to contain eight transmembrane domains. In humans, the gene for HMG-CoA reductase (NADPH) is located on the long arm of the fif ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
HMG-CoA Synthase
In biochemistry, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis. The 3 substrates of this enzyme are acetyl-CoA, H2O, and acetoacetyl-CoA, whereas its two products are (''S'')-3-hydroxy-3-methylglutaryl-CoA and CoA. In humans, the protein is encoded by the ''HMGCS1'' gene on chromo ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Mevalonate Pathway
The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones. The mevalonate pathway begins with acetyl-CoA and ends with the production of IPP and DMAPP. It is best known as the target of statins, a class of cholesterol lowering drugs. Statins inhibit HMG-CoA reductase within the mevalonate pathway. Upper mevalonate pathway The mevalonate pathway of eukaryotes, archaea, and eubacteria all begin the same way. The sole carbon feed stock of the pathway is acetyl-CoA. The first step condenses two acetyl-CoA molecules to yield acetoacetyl-CoA. This is followed by a second condensation to form ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
HMG-CoA Lyase
3-Hydroxy-3-methylglutaryl-CoA lyase (or HMG-CoA lyase) is an enzyme ( that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis (ketone body formation). It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine. Structure The HMGCL gene encodes a 34.5-kDa protein that is localized to the mitochondrion and peroxisome. Multible isoforms of the proteins are known due to alternative splicing. The major isoform (isoform 1) is most highly expressed in the liver whereas isoform 2 is found in energy-demanding tissues including the brain, heart, and skeletal muscle. Structure of the HMGCL protein has been resolved by X-ray crystallography at 2.1-Ã… resolution, and reveals that the protein may function as a dimer. Substrate access to the active site of the HMGCL enzyme involves substrate binding across ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)#Eukaryotic cells, cells and is an essential structural and cholesterol signaling, signaling component of animal cell membranes. In vertebrates, hepatocyte, hepatic cells typically produce the greatest amounts. In the brain, astrocytes produce cholesterol and transport it to neurons. It is absent among prokaryotes (bacteria and archaea), although there are some exceptions, such as ''Mycoplasma'', which require cholesterol for growth. Cholesterol also serves as a Precursor (chemistry), precursor for the biosynthesis of steroid hormones, bile acid and vitamin D. Elevated levels of cholesterol in the blood, especially when bound to low-density lipoprotein (LDL, often referred to as "bad cholesterol"), may increase the risk of ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Acetoacetyl CoA
Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for Cholesterol#Biosynthesis, cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion pathway (in the tissue), it is no longer associated with having HMG-CoA as a product or as a reactant. It is created from acetyl-CoA, a thioester, which reacts with the enolate of a second molecule of acetyl-CoA in a Claisen condensation, Claisen condensation reaction, and it is acted upon by HMG-CoA synthase to form HMG-CoA. During the metabolism of leucine, this last reaction is reversed. Some individuals may experience Acetoacetyl-CoA deficiency. This deficiency is classified as a disorder ketone body and isoleucine metabolism that can be inherited. Additional mutations include those with the enzymes within pathways related to Acetoacetyl CoA, including Beta-Ketothiolase deficiency and Mitochondrial 3-hydroxy-3- ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Acetoacetyl-CoA
Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis ( ketogenesis) pathway of the liver. In the ketone bodies digestion pathway (in the tissue), it is no longer associated with having HMG-CoA as a product or as a reactant. It is created from acetyl-CoA, a thioester, which reacts with the enolate of a second molecule of acetyl-CoA in a Claisen condensation reaction, and it is acted upon by HMG-CoA synthase to form HMG-CoA. During the metabolism of leucine, this last reaction is reversed. Some individuals may experience Acetoacetyl-CoA deficiency. This deficiency is classified as a disorder ketone body and isoleucine metabolism that can be inherited. Additional mutations include those with the enzymes within pathways related to Acetoacetyl CoA, including Beta-Ketothiolase deficiency and Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase mutation. Add ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ketogenesis
Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others. (In rare metabolic diseases, insufficient gluconeogenesis can cause excessive ketogenesis and hypoglycemia, which may lead to the life-threatening condition known as non-diabetic ketoacidosis.) Ketone bodies are not obligately produced from fatty acids; rather a meaningful amount of them is synthesized only in a situation of carbohydrate and protein insufficiency, where only fatty acids are readily available as fuel for their production. Recent evidence suggests that glial cells are ketogenic, supplying neurons with locally synthesized ketone bodies to sustain cognitive processes. Production Ketone bodies are produced mainly in the mitochondria of liver cell ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
β-methylglutaconyl-CoA
3-Methylglutaconyl-CoA (MG-CoA), also known as β-methylglutaconyl-CoA, is an intermediate in the metabolism of leucine. It is metabolized into HMG-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate pathway, mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase .... Leucine metabolism See also * Methylcrotonyl-CoA carboxylase * Methylglutaconyl-CoA hydratase References Organophosphates Thioesters of coenzyme A {{biochem-stub ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Mevalonate
Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate'' and is of major pharmaceutical importance. Drugs like statins (which lower levels of cholesterol) stop the production of mevalonate by inhibiting HMG-CoA reductase. Chemistry Mevalonic acid is very soluble in water and polar organic solvents. It exists in equilibrium with its lactone form, called mevalonolactone, that is formed by internal condensation of its terminal alcohol and carboxylic acid functional groups. Mevalonolactone acts to correct statin linked myopathy and limb girdle muscular disease caused by HMG CoA reductase mutation. Biology Mevalonic acid is a precursor in the biosynthetic pathway known as the mevalonate pathway that produces terpenes and steroids. Mevalonic acid is the primary precursor of isopentenyl pyroph ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
