Cholesterol-Mediated Coenzyme A Depletion in Catabolic Mutants of Mycobacteria Leads to Toxicity.
ACS Infect Dis
; 10(1): 107-119, 2024 Jan 12.
Article
en En
| MEDLINE
| ID: mdl-38054469
ABSTRACT
Cholesterol is a critical growth substrate for Mycobacterium tuberculosis (Mtb) during infection, and the cholesterol catabolic pathway has been targeted for the development of new antimycobacterial agents. A key metabolite in cholesterol catabolism is 3aα-H-4α(3'-propanoate)-7aß-methylhexahydro-1,5-indanedione (HIP). Many of the HIP metabolites are acyl-coenzyme A (CoA) thioesters, whose accumulation in deletion mutants can cause cholesterol-mediated toxicity. We used LC-MS/MS analysis to demonstrate that deletion of genes involved in HIP catabolism leads to acyl-CoA accumulation with concomitant depletion of free CoASH, leading to dysregulation of central metabolic pathways. CoASH and acyl-CoAs inhibited PanK, the enzyme that catalyzes the first step in the transformation of pantothenate to CoASH. Inhibition was competitive with respect to ATP with Kic values ranging from 9 µM for CoASH to 57 µM for small acyl-CoAs and 180 ± 30 µM for cholesterol-derived acyl-CoA. These findings link two critical metabolic pathways and suggest that therapeutics targeting cholesterol catabolic enzymes could both prevent the utilization of an important growth substrate and simultaneously sequester CoA from essential cellular processes, leading to bacterial toxicity.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Espectrometría de Masas en Tándem
/
Mycobacterium tuberculosis
Idioma:
En
Revista:
ACS Infect Dis
Año:
2024
Tipo del documento:
Article
País de afiliación:
Canadá