3,4-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione 4,5-dioxygenase (HsaC)

3,4-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione 4,5-dioxygenase, commonly known as HsaC, is an iron-dependent extradiol dioxygenase primarily found in actinobacteria such as Mycobacterium tuberculosis (UniProt: P9WNS3). It plays a pivotal role in the cholesterol degradation pathway, specifically catalyzing the oxidative cleavage of the A-ring of 3,4-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione (DHSA) into 4,5-9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-dien-4-oate (Yam et al., 2009, PubMed: 19147488). This metabolic step is essential for the survival and persistence of M. tuberculosis within host macrophages, where cholesterol serves as a major carbon and energy source (Casabon et al., 2013, PubMed: 23813443). Because the cholesterol ring-cleavage pathway is unique to bacteria and absent in humans, HsaC is considered a high-priority target for the development of narrow-spectrum antibiotics (Dresen et al., 2010, PubMed: 20651117). Inhibition of HsaC not only starves the bacterium of energy but also leads to the accumulation of catechol intermediates that are inherently toxic to the pathogen (Thomas et al., 2011, PubMed: 21908668). Current research focuses on developing substrate analogs and small-molecule inhibitors to disrupt this pathway and treat multi-drug resistant tuberculosis. The enzyme's structure features a non-heme Fe(II) center, which provides a specific site for the design of competitive inhibitors (Yam et al., 2009, PubMed: 19147488).

Other names

HsaC3,4-DHSA dioxygenaseCatechol 4,5-dioxygenaseSteroid ring-cleaving dioxygenase3,4-dihydroxy-9,10-secoandrosta-1,3,5-triene-9,17-dione 4,5-dioxygenase

Inhibition of cholesterol catabolism in Mycobacterium tuberculosis leading to metabolic arrest and accumulation of toxic catechol intermediates