methylcrotonoyl-CoA carboxylase | |||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | methylcrotonyl-CoA carboxylase3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)beta-methylcrotonyl coenzyme A carboxylaseMCCCmethylcrotonyl coenzyme A carboxylasebeta-methylcrotonyl CoA carboxylasebeta-methylcrotonyl-CoA carboxylase | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | GeneCards: [1]; OMA:- orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
Methylcrotonoyl-coenzyme A carboxylase 1 (alpha) | |||||||
---|---|---|---|---|---|---|---|
Identifiers | |||||||
Symbol | MCCC1 | ||||||
NCBI gene | 56922 | ||||||
HGNC | 6936 | ||||||
OMIM | 609010 | ||||||
RefSeq | NM_020166 | ||||||
UniProt | Q96RQ3 | ||||||
Other data | |||||||
EC number | 6.4.1.4 | ||||||
Locus | Chr. 3 q27.1 | ||||||
|
Methylcrotonoyl-coenzyme A carboxylase 2 (beta) | |||||||
---|---|---|---|---|---|---|---|
Identifiers | |||||||
Symbol | MCCC2 | ||||||
NCBI gene | 64087 | ||||||
HGNC | 6937 | ||||||
OMIM | 609014 | ||||||
RefSeq | NM_022132 | ||||||
UniProt | Q9HCC0 | ||||||
Other data | |||||||
EC number | 6.4.1.4 | ||||||
Locus | Chr. 5 q12-q13 | ||||||
|
Methylcrotonyl CoA carboxylase (EC 6.4.1.4, MCC) (3-methylcrotonyl CoA carboxylase, methylcrotonoyl-CoA carboxylase) is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid.[1]
Human MCC is a biotin dependent mitochondrial enzyme formed by the two subunits MCCCα and MCCCβ, encoded by MCCC1 and MCCC2 respectively.[2] MCCC1 gene has 21 exons and resides on chromosome 3 at q27.[3] MCCC2 gene has 19 exons and resides on chromosome 5 at q12-q13.[4]
The enzyme contains α and β subunits. Human MCCCα is composed of 725 amino acids which harbor a covalently bound biotin essential for the ATP-dependent carboxylation; MCCCβ has 563 amino acids that possess carboxyltransferase activity which presumably is essential for binding to 3-methylcrotonyl CoA.[5] The MCC holoenzyme is thought to be a heterododecamer (6α6β) with close structural analogytopropionyl-CoA carboxylase (PCC), another biotin dependent mitochondrial carboxylase.[6]
During branched-chain amino acid degradation, MCC performs a single step in the breakdown of leucine to eventually yield acetyl CoA and acetoacetate.[7] MCC catalyzes the carboxylation of 3-methylcrotonyl CoAto3-methylglutaconyl CoA, a critical step for leucine and isovaleric acid catabolism in species including mammals, plants and bacteria.[8] 3-Methylglutaconyl CoA is then hydrated to produce 3-hydroxy-3-methylglutaryl CoA. 3-Hydroxy-3-methylglutaryl CoA is cleaved into two molecules, acetoacetate and acetyl CoA.
Point mutations and deletion events in the genes coding for MCC can lead to MCC deficiency, an inborn error of metabolism which usually presents with vomiting, metabolic acidosis, very low plasma glucose concentration, and very low levels of carnitine in plasma.[9]
Muscle: α-Ketoisocaproate (α-KIC)
Liver: α-Ketoisocaproate (α-KIC)
Excreted
in urine (10–40%)
β-Hydroxy β-methylglutaryl-CoA
(HMG-CoA)
β-Methylcrotonyl-CoA
(MC-CoA)
β-Methylglutaconyl-CoA
(MG-CoA)
MC-CoA
carboxylase
Unknown
Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.[10][11][12] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[10][11][12]
enzyme |
Bicarbonate is activated by the addition of ATP, increasing the reactivity of bicarbonate. Once bicarbonate is activated, the biotin portion of MCC performs nucleophilic attack on the activated bicarbonate to form enzyme-bound carboxybiotin. The carboxybiotin portion of MCC can then undergo nucleophilic attack transferring the carboxyl group to the substrate, 3-methylcrotonyl CoA, to form 3-methylglutaconyl CoA.[7]
MCC is covalently modified and inhibited by intermediates of leucine catabolism including 3-methylglutaconyl-CoA, 3-methylglutaryl-CoA, and 3-hydroxy-3-methylglutaryl-CoA that act as reactive acyl species on MCC in a negative feedback loop. SIRT4 activates MCC and upregulates leucine catabolism by removing acyl residues that modified MCC.[13]
In humans, MCC deficiency is a rare autosomal recessive genetic disorder whose clinical presentations range from benign to profound metabolic acidosis and death in infancy. Defective mutations in either the α or β subunit have been shown to cause the MCC-deficient syndrome.[5] The typical diagnostic test is the elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Patients with MCC deficiency usually have normal growth and development before the first acute episode, such as convulsionsorcoma, that usually occurs between the age of 6-months to 3-years.[14]
MCC has been shown to interact with TRI6 in Fusarium graminearum.[15]
HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).
Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
| |||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Essential amino acids are in Capitals | |||||||||||||||||||||||||||||||||||||||||||
K→acetyl-CoA |
| ||||||||||||||||||||||||||||||||||||||||||
G |
|
| |
---|---|
Biotin dependent carboxylation |
|
Other |
|
| |
---|---|
Activity |
|
Regulation |
|
Classification |
|
Kinetics |
|
Types |
|