Fumarate hydratase (FH) (FH)

Bacterial fumarate hydratase is an essential metabolic enzyme that catalyzes the reversible hydration of fumarate to L-malate within the tricarboxylic acid (TCA) cycle [UniProt: P0AC33]. In bacteria, these enzymes are classified into two distinct groups: Class I (iron-sulfur cluster-dependent, e.g., FumA and FumB) and Class II (metal-independent, e.g., FumC) [PubMed: 31233711]. Class I fumarases are particularly attractive as therapeutic targets because they have no structural homologs in humans, allowing for the design of highly selective antimicrobial agents [PubMed: 25654381]. Inhibition of this enzyme leads to the depletion of malate and the accumulation of fumarate, effectively stalling energy production and biosynthetic precursors necessary for bacterial survival [PubMed: 16430314]. This target is of significant interest for treating persistent infections such as those caused by Mycobacterium tuberculosis and Helicobacter pylori [PubMed: 25654381, 16430314]. While no FDA-approved drugs currently target this enzyme, research into small-molecule inhibitors like mercaptosuccinate and pyromellitic acid continues to demonstrate potential for novel antibiotic development [PubMed: 31233711]. The enzyme's dual role in aerobic and anaerobic metabolism further enhances its value as a target for broad-spectrum or niche-specific antibacterials [UniProt: P05042].

Other names

FumaraseL-malate hydro-lyaseFumAFumBFumC

Inhibition of the reversible hydration of fumarate to L-malate, disrupting the tricarboxylic acid (TCA) cycle and bacterial energy metabolism.