Malonyl-CoA is a

coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric ac ...

derivative of

malonic acid Malonic acid is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's diethyl ester. The name originates from ...

Biosynthesis

Malonyl-CoA cannot cross

membranes A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

and there is no known malonyl-CoA import mechanism. The

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

therefore takes place locally: *

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

: Malonyl-CoA is formed by carboxylating

acetyl-CoA Acetyl-CoA (acetyl coenzyme A) 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 (Krebs cycle) to be oxidation, o ...

using the highly regulated enzyme acetyl-CoA carboxylase 1 (ACC1). One molecule of acetyl-CoA joins with a molecule of

bicarbonate In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula . Bicarbonate serves a crucial bioche ...

, requiring energy rendered from ATP. * Mitochondrial outer membrane: Malonyl-CoA is formed by carboxylating

using the highly regulated enzyme acetyl-CoA carboxylase 2 (ACC2). The reaction is the same as with ACC1. *

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. It can also be referred as the mitochondrial fluid. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitoc ...

: Malonyl-CoA is formed in coordinated fashion by mtACC1, a mitochondrial

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

of ACC1, and acyl-CoA synthetase family member 3 (ACSF3), a mitochondrial malonyl-CoA synthetase. MtACC1, like cytosolic ACC1 catalyses the carboxylation of acetyl-CoA, while ACSF3 catalyses the

thioester In organic chemistry, thioesters are organosulfur compounds with the molecular structure . They are analogous to carboxylate esters () with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix ...

ification of

malonate The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Anions ...

. The latter serves for the clearance of mitochondrial malonate, since malonate is a potent

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

of mitochondrial respiration as it competitively inhibits

succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...

. However, the source of malonyl-CoA in the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

is still up for debate.

Functions

It plays a key role in chain elongation in fatty acid biosynthesis and

polyketide In organic chemistry, polyketides are a class of natural products derived from a Precursor (chemistry), precursor molecule consisting of a Polymer backbone, chain of alternating ketone (, or Carbonyl reduction, its reduced forms) and Methylene gro ...

biosynthesis.

Cytosolic malonyl-CoA

Malonyl-CoA provides 2-carbon units to fatty acids and commits them to fatty acid chain synthesis. Malonyl-CoA is utilised in fatty acid biosynthesis by the enzyme malonyl coenzyme A:acyl carrier protein transacylase (MCAT). MCAT serves to transfer

malonate The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Anions ...

from malonyl-CoA to the terminal

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

of ''holo''- acyl carrier protein (ACP). Malonyl-CoA is a highly regulated molecule in fatty acid synthesis; as such, it inhibits the rate-limiting step in

beta-oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...

of fatty acids. Malonyl-CoA inhibits

fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

from associating with

carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for f ...

by regulating the enzyme carnitine palmitoyltransferase, thereby preventing them from entering the

, where fatty acid oxidation and degradation occur.

Polyketide biosynthesis

MCAT is also involved in bacterial

biosynthesis. The enzyme MCAT together with an acyl carrier protein (ACP), and a

polyketide synthase Polyketide synthases (PKSs) are a family of multi- domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share ...

(PKS) and chain-length factor heterodimer, constitutes the minimal PKS of type II polyketides.

Clinical relevance

Malonyl-CoA plays a special role in the mitochondrial clearance of toxic malonic acid in the metabolic disorders

combined malonic and methylmalonic aciduria Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. However, the methylmalonic ...

(CMAMMA) and malonic aciduria. In CMAMMA, malonyl-CoA synthetase, ACSF3 is impaired, which generates mitochondrial malonyl-CoA from malonic acid, which can then be converted to acetyl-CoA by

malonyl-CoA decarboxylase Malonyl-CoA decarboxylase (), (which can also be called MCD and malonyl-CoA carboxyl-lyase) is found in bacteria and humans and has important roles in regulating fatty acid metabolism and food intake, and it is an attractive target for drug discove ...

. In contrast, in malonic aciduria, malonyl-CoA decarboxylase is decreased, which converts malonyl-CoA to acetyl-CoA.

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References

External links

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{{DEFAULTSORT:Malonyl-Coa Metabolism Thioesters of coenzyme A