methylcrotonyl-CoA carboxylase3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)beta-methylcrotonyl coenzyme A carboxylaseMCCCmethylcrotonyl coenzyme A carboxylasebeta-methylcrotonyl CoA carboxylasebeta-methylcrotonyl-CoA carboxylase
Methylcrotonyl CoA carboxylase (
EC6.4.1.4, 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]
Structure
Gene
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]
Protein
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
analogy to
propionyl-CoA carboxylase (PCC), another biotin dependent mitochondrial
carboxylase.[6]
Function
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 CoA to
3-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.
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]
Regulation
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]
Clinical significance
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
convulsions or
coma, that usually occurs between the age of 6-months to 3-years.[14]
^Morscher RJ, Grünert SC, Bürer C, Burda P, Suormala T, Fowler B, Baumgartner MR (Apr 2012). "A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency". Molecular Genetics and Metabolism. 105 (4): 602–6.
doi:
10.1016/j.ymgme.2011.12.018.
PMID22264772.
^
abHolzinger A, Röschinger W, Lagler F, Mayerhofer PU, Lichtner P, Kattenfeld T, Thuy LP, Nyhan WL, Koch HG, Muntau AC, Roscher AA (Jun 2001). "Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency". Human Molecular Genetics. 10 (12): 1299–306.
doi:
10.1093/hmg/10.12.1299.
PMID11406611.
^Chu CH, Cheng D (Jun 2007). "Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC)". Protein Expression and Purification. 53 (2): 421–7.
doi:
10.1016/j.pep.2007.01.012.
PMID17360195.
^Stipanuk MH (2000). Biochemical and physiological aspects of human nutrition. Philadelphia, Pa.: Saunders. pp. 535–6.
ISBN978-0-7216-4452-3.
^
abZanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011).
"HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025.
doi:
10.1007/s00726-010-0678-0.
PMID20607321.
S2CID11120110. 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).
^
abKohlmeier M (May 2015).
"Leucine".
Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388.
ISBN978-0-12-387784-0. Retrieved 6 June 2016. 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 Figure 8.57: Metabolism of L-leucine