Methyl crotonoyl-CoA carboxylase
| Methylcrotonoyl-CoA carboxylase 1 (α-subunit) | ||
|---|---|---|
| Properties of human protein | ||
| Mass / length primary structure | 725 AA | |
| Cofactor | Biotin | |
| Identifier | ||
| Gene names | MCCC1 (MCCA) | |
| External IDs |
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| Enzyme classification | ||
| EC, category | 6.4.1.4 , ligase | |
| Response type | Carboxylation | |
| Substrate | 3-methylcrotonoyl-CoA + HCO 3 - + ATP | |
| Products | 3-methylglutaconyl-CoA + ADP + P i | |
| Occurrence | ||
| Homology family | MCCC1 | |
| Parent taxon | Creature | |
| Methylcrotonoyl-CoA carboxylase 2 (β subunit) | ||
|---|---|---|
| Properties of human protein | ||
| Mass / length primary structure | 563 AA | |
| Identifier | ||
| Gene names | MCCC2 (MCCB) | |
| External IDs |
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|
| Enzyme classification | ||
| EC, category | 6.4.1.4 , ligase | |
| Response type | Carboxylation | |
| Substrate | 3-methylcrotonoyl-CoA + HCO 3 - + ATP | |
| Products | 3-methylglutaconyl-CoA + ADP + P i | |
| Occurrence | ||
| Homology family | AccD / PCCB | |
| Parent taxon | Creature | |
The methylcrotonyl-coa carboxylase is an enzyme which the class of ligases counts and in the mitochondria found of animals and plants as well as bacteria. Other names are methylcrotonyl-CoA carboxylase or MCCase or MCC for short . CoA is coenzyme A . It is encoded by the MCCC1 gene .
The methylcrotonoyl-CoA carboxylase makes the amino acid leucine usable for the energy supply of the organism. Leucine is an important nutrient for muscles , especially during heavy exercise or during fasting periods. The enzyme needs the vitamin biotin to function . A defect in one of the two subunits leads to a rare metabolic disorder.
structure
The methylcrotonoyl-CoA carboxylase forms a heteromer, i.e. it consists of two different subunits. The larger α-subunit contains the prosthetic group biotin and houses the docking site for adenosine triphosphate (ATP) as well as the domain at which biotin is carboxylated. The smaller β-subunit contains the domain where the carboxy group is transferred from the biotin to the substrate.
function
The methylcrotonoyl-CoA carboxylase catalyzes the fourth reaction step in the breakdown of the amino acid leucine to the versatile metabolic intermediates acetyl-CoA and acetoacetate . A carboxy group is bound to 3-methylcrotonoyl-CoA with consumption of one molecule of ATP and 3-methylglutaconyl-CoA is formed. The carboxy group is transferred by biotin, which is covalently linked to the rest of the protein via the amino acid lysine . As on a long arm, the biotin can swing back and forth between the two active centers of the enzyme. At the active center of the α subunit, biotin is carboxylated with consumption of ATP, and the carboxy group is transferred to the substrate at the second active center, which is located in the β subunit. This mechanism is also found in the other biotin-dependent carboxylases , such as pyruvate carboxylase , propionyl-CoA carboxylase and acetyl-CoA carboxylase .
regulation
The knowledge about the control of the methylcrotonoyl-CoA-carboxlase by the organism is still very fragmentary, but it is considered certain that there are certain dependencies and regulatory mechanisms. The following examples are intended to provide a brief overview.
Gene expression
- In human cells, an increase in gene transcription as well as in cell cycle in vitro
Measured enzyme activity of methylcrotonoyl-CoA carboxylase.
- In healthy test subjects, if there is an excess of biotin, the transcription of the gene for the α-subunit increases many times over. With a slight biotin deficiency it decreases slightly, although a stronger biotin deficiency does not lead to a decrease in transcription in vitro . The authors of both articles sum up that the results, in comparison with thematically similar work by their own working groups and other groups, strongly depend on the experimental conditions. The existence of opposing regulatory mechanisms is discussed.
- Arabidopsis plants ( throat cress ) react to a state of starvation, caused by deprivation of lighting or CO 2 , with increased expression of the genes of the two subunits of methylcrotonoyl-CoA carboxylase. A biotin deficiency suppresses the increase in gene transcription when hungry.
Biotinylation of the enzyme
Depending on the tissue, tomato plants control the activity of methylcrotonoyl-CoA carboxylase by biotinylating the enzyme. (If no biotin is bound to the α-subunit, the enzyme remains inactive.) Approximately equal amounts of the α-subunit were found in roots and leaves, but the enzyme activity in the leaves was only 10% of the activity in the roots. Although free biotin is abundant in the leaves, it has been shown that this difference is due to less biotinylation of the α-subunit of the enzyme in the leaf tissue.
genetics
In humans, the gene for the α subunit codes on chromosome 3 in region q27.1, while the gene for the β subunit is found on chromosome 5 in region q12-q13.
A defect in one of the two subunits leads to a rare metabolic disorder called methylcrotonoyl-CoA carboxylase deficiency . The inheritance is usually autosomal recessive , but cases with a dominant defect are also known. The connection between genotype and phenotype is largely unexplained , i.e. why two people with the same genetic defect have different degrees of disease.
Individual evidence
- ↑ a b J. M. Berg, JL Tymoczko, L. Stryer: Biochemie. 6th edition 2007; Spectrum Academic Publishing House, Elsevier GmbH, Munich; P. 745f
- ↑ BRENDA enzyme database , entry EC 6.4.1.4
- ↑ UniProt Q96RQ3 protein database
- ↑ Protein database UniProt Q9HCC0
- ↑ JS Stanley, DM Mock, JB Griffin, J. Zempleni: Biotin uptake into human peripheral blood mononuclear cells increases early in the cell cycle, increasing carboxylase activities. In: J. Nutr. 132 (7); July 2002, pp. 1854–9 PMID 12097659 (full text)
- ^ S. Wiedmann, JD Eudy, J. Zempleni: Biotin supplementation increases expression of genes encoding interferon-gamma, interleukin-1beta, and 3-methylcrotonyl-CoA carboxylase, and decreases expression of the gene encoding interleukin-4 in human peripheral blood mononuclear cells. In: J. Nutr. 133 (3); March 2003: pp. 716–9 PMID 12612142 (full text)
- ↑ TI Vlasova, SL Stratton, AM Wells, NI Mock, DM Mock: Biotin deficiency reduces expression of SLC19A3, a potential biotin transporter, in leukocytes from human blood. In: J. Nutr. 135 (1); Jan 2005: pp. 42–7 PMID 15623830 (full text)
- ↑ P. Che, ES Wurtele, BJ Nikolau: Metabolic and environmental regulation of 3-methylcrotonyl-coenzyme A carboxylase expression in Arabidopsis. In: Plant Physiol. 129 (2); June 2002: pp. 625–637 PMID 12068107 (full text)
- ↑ P. Che, LM Weaver, ES Wurtele, BJ Nikolau: The role of biotin in regulating 3-methylcrotonyl-coenzyme a carboxylase expression in Arabidopsis. In: Plant Physiol. 131 (3); Mar 2003: pp. 1479–86 PMID 12644697 (full text)
- ↑ X. Wang, ES Wurtele, BJ Nikolau: Regulation of [beta] -Methylcrotonyl-Coenzyme A Carboxylase Activity by Biotinylation of the Apoenzyme. In: Plant Physiol. 108 (3); July 1995: pp. 1133–1139 PMID 12228532 (full text)
- ↑ HUGO gene database, entry MCCC1
- ↑ HUGO gene database, entry MCCC2
- ^ MCCC1. In: Online Mendelian Inheritance in Man . (English)
- ↑ MCCC2. In: Online Mendelian Inheritance in Man . (English)
- ↑ MR Baumgartner: Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency. In: J. Inherit. Metab. Dis. 28 (3); May 2005: pp. 301-9 PMID 15868465
- ↑ MF Dantas, T. Suormala, A. Randolph, D. Coelho, B. Fowler, D. Valle, MR Baumgartner: 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening. In: Hum. Mutat. 26 (2); Aug 2005, Epub. July 2005: p. 164. PMID 16010683
