The cryo-EM structure of trypanosome 3-methylcrotonyl-CoA carboxylase provides mechanistic and dynamic insights into its enzymatic function.
Structure
; 32(7): 930-940.e3, 2024 Jul 11.
Article
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| MEDLINE
| ID: mdl-38593794
ABSTRACT
3-Methylcrotonyl-CoA carboxylase (MCC) catalyzes the two-step, biotin-dependent production of 3-methylglutaconyl-CoA, an essential intermediate in leucine catabolism. Given the critical metabolic role of MCC, deficiencies in this enzyme lead to organic aciduria, while its overexpression is linked to tumor development. MCC is a dodecameric enzyme composed of six copies of each α- and ß-subunit. We present the cryo-EM structure of the endogenous MCC holoenzyme from Trypanosoma brucei in a non-filamentous state at 2.4 Å resolution. Biotin is covalently bound to the biotin carboxyl carrier protein domain of α-subunits and positioned in a non-canonical pocket near the active site of neighboring ß-subunit dimers. Moreover, flexibility of key residues at α-subunit interfaces and loops enables pivoting of α-subunit trimers to partly reduce the distance between α- and ß-subunit active sites, required for MCC catalysis. Our results provide a structural framework to understand the enzymatic mechanism of eukaryotic MCCs and to assist drug discovery against trypanosome infections.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Trypanosoma brucei brucei
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Proteínas Protozoarias
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Ligasas de Carbono-Carbono
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Microscopía por Crioelectrón
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Dominio Catalítico
Idioma:
En
Revista:
Structure
Asunto de la revista:
BIOLOGIA MOLECULAR
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BIOQUIMICA
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BIOTECNOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
España