Family

Sirohaem synthase (IPR012409)

Short name: Sirohaem_synth

Family relationships

None.

Description

Sirohaem synthase (CysG), a multifunctional enzyme of the sirohaem and cobalamin (vitamin B12) biosynthesis pathways, represents a fusion between uroporphyrin-III C-methyltransferase (SUMT) and precorrin-2 oxidase/chelatase. Therefore, in some bacteria, all four reactions of sirohaem biosynthesis are catalysed by one multifunctional enzyme, sirohaem synthase [PMID: 8243665].

Sirohaem and cobalamin are related macrocyclic structures derived from uroporphyrinogen III by C-methylation of the tetrapyrrole framework. All biologically important modified tetrapyrroles (including also haem and chlorophyll) share a common biosynthetic pathway up to the synthesis of the first macrocyclic intermediate, uroporphyrinogen III [PMID: 12196148]. Then, SUMT (corresponding to the C-terminal (CysGA) domain of CysG ([PMID: 7945210]) catalyses C-methylation of uroporphyrinogen III (EC:2.1.1.107). It transfers two methyl groups from S-adenosyl-L-methionine to the C-2 and C-7 atoms of uroporphyrinogen III to yield precorrin-2 via the intermediate formation of precorrin-1. SUMT is the first enzyme committed to the biosynthesis of either sirohaem or cobalamin rather than haem, and precorrin-2 is the last common intermediate in the biosynthesis of corrinoids such as cobalamin, sirohaem and coenzyme F430 [PMID: 12196148]. SUMT belongs to the domain superfamily of tetrapyrrole (corrin/porphyrin) methylases (IPR000878), which includes methylases that use S-AdoMet in the methylation of diverse substrates.

In sirohaem biosynthesis, the next two steps are beta-NAD(+)-dependent dehydrogenation of precorrin-2 to generate sirohydrochlorin followed by ferrochelation to yield sirohaem [PMID: 10051442, PMID: 9461500]. Both of these steps are performed by precorrin-2 oxidase/ferrochelatase. In sirohaem synthase CysG, it corresponds to the N-terminal (CysGB) domain [PMID: 10051442, PMID: 9461500]. Ferrochelation can also be performed by CbiK (PIRSF033579) [PMID: 9150215] or by SirB [PMID: 12408752] or CbiX [PMID: 12686546] (PIRSF004877).

In the anaerobic cobalamin biosynthesis (e.g., in Salmonella typhimurium), a cobaltochelatase produces cobalt-precorrin-2. This cobaltochelation can be performed by CbiK [PMID: 9150215] or by CbiX [PMID: 12917443, PMID: 12686546], but also by CysGB homologues [PMID: 8955319], even though this is not their primary function [PMID: 9461500]. Therefore, CysGB can essentially duplicate the function of an unrelated chelatase, CbiK [PMID: 8955319, PMID: 9150215]. Note that in the aerobic cobalamin biosynthesis, cobalt insertion occurs in a later, different step (see PIRSF031715).

Precorrin-2 oxidase/chelatases are not similar in sequence or structural fold to any other known chelatases or oxidases [PMID: 11980703, PMID: 10051442]. Analysis of mutant proteins suggests that both catalytic activities share a single active site cleft formed between the N-terminal NAD-binding subdomain and the central subdomain [PMID: 11980703]. Therefore, they can be considered as the third class of cobalt chelatases, in addition to class I (ATP-dependent, aerobic pathway PIRSF031715) and class II (ATP-independent, anaerobic pathway PIRSF033579) [PMID: 12686546, PMID: 8905078]. As with the class II chelatases, they do not require ATP for activity. However, they are not structurally similar to class II chelatases, and it is likely that they have arisen by the acquisition of a chelatase function within a dehydrogenase catalytic framework [PMID: 11980703, PMID: 12686546].

GO terms

Biological Process

GO:0009236 cobalamin biosynthetic process
GO:0055114 oxidation-reduction process
GO:0019354 siroheme biosynthetic process

Molecular Function

GO:0051287 NAD binding
GO:0043115 precorrin-2 dehydrogenase activity
GO:0051266 sirohydrochlorin ferrochelatase activity
GO:0004851 uroporphyrin-III C-methyltransferase activity

Cellular Component

No terms assigned in this category.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
HAMAP
PIRSF