Zinc-independent folate biosynthesis: genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB.

Full Abstract

GTP cyclohydrolase I (GCYH-I) is an essential Zn(2+)-dependent enzyme that catalyzes the first step of the de novo folate biosynthetic pathway in bacteria and plants, the 7-deazapurine biosynthetic pathway in Bacteria and Archaea, and the biopterin pathway in mammals. We recently reported the discovery of a new prokaryotic-specific GCYH-I (GCYH-IB) that displays no sequence identity to the canonical enzyme and is present in approximately 25% of bacteria, the majority of which lack the canonical GCYH-I (renamed GCYH-IA). Genomic and genetic analyses indicate that in those organisms possessing both enzymes, e.g., Bacillus subtilis, GCYH-IA and -IB are functionally redundant, but differentially expressed. Whereas GCYH-IA is constitutively expressed, GCYH-IB is expressed only under Zn(2+)-limiting conditions. These observations are consistent with the hypothesis that GCYH-IB functions to allow folate biosynthesis during Zn(2+) starvation. Here, we present biochemical and structural data showing that bacterial GCYH-IB, like GCYH-IA, belongs to the tunneling-fold (T-fold) superfamily. However, the GCYH-IA and -IB enzymes exhibit significant differences in global structure and active-site architecture. While GCYH-IA is a unimodular, homodecameric, Zn(2+)-dependent enzyme, GCYH-IB is a bimodular, homotetrameric enzyme activated by a variety of divalent cations. The structure of GCYH-IB and the broad metal dependence exhibited by this enzyme further underscore the mechanistic plasticity that is emerging for the T-fold superfamily. Notably, while humans possess the canonical GCYH-IA enzyme, many clinically important human pathogens possess only the GCYH-IB enzyme, suggesting that this enzyme is a potential new molecular target for antibacterial development.

Author information

Author/s: Sankaran, Banumathi (B); Bonnett, Shilah A (SA); Shah, Kinjal (K); Gabriel, Scott (S); Reddy, Robert (R); Schimmel, Paul (P); Rodionov, Dmitry A (DA); de Crécy-Lagard, Valérie (V); Helmann, John D (JD); Iwata-Reuyl, Dirk (D); Swairjo, Manal A (MA);

Affiliation: Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.

Grants: GM059323 (Agency:NIGMS NIH HHS) ; GM15539 (Agency:NIGMS NIH HHS) ; GM70641 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of bacteriology (J Bacteriol), published in United States. (Language: eng)

Reference: 2009-Nov; vol 191 (issue 22) : pp 6936-49

Dates: Created 2009/10/28; Completed 2009/11/17;

PMID: 19767425, status: MEDLINE (last retrieved date: 11/17/2009)

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