Mycobacterial fatty acid synthase I (FAS I)

Mycobacterial fatty acid synthase I (FAS I) is a multifunctional, large enzymatic complex essential for the survival and virulence of Mycobacterium tuberculosis. Unlike most prokaryotes, which use a type II (dissociated, monofunctional) FAS system, mycobacteria possess a type I (eukaryote-like, multifunctional, single-peptide-chain) fatty acid synthase for de novo biosynthesis of long-chain fatty acyl-CoAs. These acyl chains provide the building blocks for complex mycolic acids, which are critical structural components of the mycobacterial cell envelope and major contributors to its impermeability and resistance to antibiotics. FAS I is considered a validated drug target for tuberculosis treatment due to its essentiality and its unique structure compared to human FAS, offering selectivity for inhibitor development. FAS I is targeted by pyrazinamide and analogs, which competitively inhibit enzymatic activity, thereby blocking mycolic acid synthesis and leading to cell death. Structural and functional distinctions set mycobacterial FAS I apart from homologous fungal and human enzymes, supporting ongoing structure-guided drug discovery campaigns[2][4][5][6][7].

Other names

Fatty acid synthase IFAS-IType I fatty acid synthaseMycobacterium tuberculosis FAS-IfasI gene product (Rv2524c in M. tuberculosis)

Competitive inhibition of the enzymatic activity (as shown for PZA and analogs), preventing de novo fatty acid synthesis needed for cell envelope/mycolic acid construction