Coproporphyrinogen III dehydrogenase (CPDH)

Coproporphyrinogen III dehydrogenase (CPDH), also known as HemN or oxygen-independent coproporphyrinogen III oxidase, is a radical S-adenosyl-L-methionine (SAM) enzyme essential for heme biosynthesis under anaerobic or microaerobic conditions [1, 2]. It catalyzes the oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX, a critical step in the production of heme and chlorophyll [1, 7]. Unlike the oxygen-dependent oxidase (CPOX) found in humans, CPDH utilizes a [4Fe-4S] cluster and SAM to perform the reaction without molecular oxygen [1, 11]. This enzyme is a vital metabolic component for various pathogenic bacteria and parasites, including Helicobacter pylori and Leishmania major, making it a potential target for novel antimicrobial therapies [4, 9]. While no FDA-approved drugs currently target CPDH, research has identified various inhibitors such as heavy metals (e.g., mercury, cadmium) and feedback inhibitors like hemin [8, 11]. Disruption of this pathway in humans (via the CPOX counterpart) leads to hereditary coproporphyria, which manifests as photosensitivity, abdominal pain, and neurological symptoms [3, 4]. Consequently, therapeutic strategies targeting bacterial CPDH must ensure high selectivity to avoid inducing porphyria-like toxicities in patients [4, 6].

Other names

Oxygen-independent coproporphyrinogen III oxidaseHemNCgdHCoproporphyrinogen-III:S-adenosyl-L-methionine oxidoreductase (decarboxylating)CPO

Inhibition of the enzymatic conversion of coproporphyrinogen III to protoporphyrinogen IX, leading to the depletion of heme and the accumulation of toxic porphyrin intermediates in pathogens.