Names | |
---|---|
IUPAC name 3′-O-Phosphonoadenosine 5′-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-{[3-oxo-3-({2-[(3-oxobutanoyl)sulfanyl]ethyl}amino)propyl]amino}butyl dihydrogen diphosphate] | |
Systematic IUPAC name O1-{[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]methyl} O3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-{[3-oxo-3-({2-[(3-oxobutanoyl)sulfanyl]ethyl}amino)propyl]amino}butyl] dihydrogen diphosphate | |
Identifiers | |
3D model (JSmol) | |
ChEBI | |
ChemSpider | |
ECHA InfoCard | 100.014.378 |
MeSH | acetoacetyl+CoA |
PubChem CID | |
CompTox Dashboard (EPA) | |
| |
| |
Properties | |
C25H40N7O18P3S | |
Molar mass | 851.61 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
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. [1] 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, [2] and it is acted upon by HMG-CoA synthase to form HMG-CoA. [1] During the metabolism of leucine, this last reaction is reversed. Some individuals may experience Acetoacetyl-CoA deficiency. [3] This deficiency is classified as a disorder ketone body and isoleucine metabolism that can be inherited.[ citation needed ] 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.
Additionally, it reacts with NADPH-dependent acetoacetyl-coenzyme A reductase, also known as PhaB, in a pathway that produces polyester polyhydroxyalkanoate (PHA). The reduction of acetoacetyl-coA by Pha creates (R)-3-hydroxybutyryl-CoA, which polymerizes to PHA. [4] The pathway is present in bacteria such as Ralstonia eutropha and the PCC6803 strain of Synechocystis. [5] Mover over, Acetoacetyl-CoA is involved with neuronal development involving lipogenesis and providing fats and cholesterol for neuronal cells.
Mitochondrial acetoacetyl-CoA thiolase, also known as thiolase II, the enzyme responsible for catalyzing the synthesis of acetoacetyl-CoA within ketogenesis as mentioned, is also involved within acetoacetyl-CoA cleavage in ketolysis. It is observed to play a role within cleavage of acetyl-CoA from acetoacetyl-CoA and 2-methylacetoacetyl-CoA. The enzyme is involved in an autosomal recessive disorders that impacts the catabolism of ketone bodies and isoleucine: beta-ketothiolase deficiency, leading to their deficiency within mitochondria. The mutation takes place within the acetoacetyl-CoA thiolase (ACAT) gene mapped on chromosome 11q22.3-23.1. [6]
Mutations in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) is another inherited autosomal recessive disorder affecting the catabolism of ketone bodies and can lead to the build-up of acetoacetyl-CoA. [7]
Acetoacetyl-CoA also behaves as a product of acetoacetyl-CoA synthetase (AACS) within the cytosol, using acetoacetate as the substrate, the reaction provides acetyl groups for lipogenesis. [8] Understanding acetoacetyl-CoA is important in cholesterol development and lipogenesis and Acetoacetyl-CoA synthetase playing a role in its development, it also plays a significant role within the brain. Cholesterol and fats have been observed in high concentrations within neuronal tissue, as well as high AACS mRNA expression levels within cells of the hippocampus and cortical region. In addition, they play a significant role in neuronal development during the early embryonic and fetal developmental stages. [9]
Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production. Coenzyme A consists of a β-mercaptoethylamine group linked to the vitamin pantothenic acid (B5) through an amide linkage and 3'-phosphorylated ADP. The acetyl group of acetyl-CoA is linked to the sulfhydryl substituent of the β-mercaptoethylamine group. This thioester linkage is a "high energy" bond, which is particularly reactive. Hydrolysis of the thioester bond is exergonic (−31.5 kJ/mol).
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.
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.
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.
Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.
β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the 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.
Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.
3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. 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.
Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway.
Acetyl-CoA acetyltransferase, mitochondrial, also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT1 gene.
3-Methylcrotonyl-CoA or β-Methylcrotonyl-CoA is an intermediate in the metabolism of leucine.
In enzymology, an acetyl-CoA C-acetyltransferase is an enzyme that catalyzes the chemical reaction
In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 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.
3-oxoacid CoA-transferase 1 (OXCT1) is an enzyme that in humans is encoded by the OXCT1 gene. It is also known as succinyl-CoA-3-oxaloacid CoA transferase (SCOT). Mutations in the OXCT1 gene are associated with succinyl-CoA:3-oxoacid CoA transferase deficiency. This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A (CoA) from succinyl-CoA to acetoacetate.
Alpha-aminoadipic semialdehyde synthase is an enzyme encoded by the AASS gene in humans and is involved in their major lysine degradation pathway. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants. In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia. This condition is inherited in an autosomal recessive pattern and is not considered a particularly negative condition, thus making it a rare disease.
3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an enzyme in humans that is encoded by the HMGCS2 gene.
Acetoacetyl-CoA synthase (EC 2.3.1.194, NphT7) is an enzyme with systematic name acetyl-CoA:malonyl-CoA C-acetyltransferase (decarboxylating). This enzyme catalyses the following chemical reaction
Succinyl-CoA ligase [GDP-forming] subunit beta, mitochondrial is an enzyme that in humans is encoded by the SUCLG2 gene on chromosome 3.