3D2O

Crystal Structure of Manganese-metallated GTP Cyclohydrolase Type IB

Summary for 3D2O

• Entry DOI: 10.2210/pdb3d2o/pdb
• Related: 3D1T
• Descriptor: UPF0343 protein NGO0387, MANGANESE (II) ION, LITHIUM ION, ... (6 entities in total)
• Functional Keywords: bimodular tunnel fold, tunneling fold, folate biosynthesis, gtp cyclohydrolase, metalloenzyme, manganese, hydrolase, biosynthetic protein
• Biological source: Neisseria gonorrhoeae
• Total number of polymer chains: 2
• Total formula weight: 57759.96

Authors

Swairjo, M.A. (deposition date: 2008-05-08, release date: 2009-05-12, Last modification date: 2023-08-30)

Primary citation

Sankaran, B.,Bonnett, S.A.,Shah, K.,Gabriel, S.,Reddy, R.,Schimmel, P.,Rodionov, D.A.,de Crecy-Lagard, V.,Helmann, J.D.,Iwata-Reuyl, D.,Swairjo, M.A.
Zinc-independent folate biosynthesis: genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB
J.Bacteriol., 191:6936-6949, 2009

PubMed 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.

PubMed: 19767425
DOI: 10.1128/JB.00287-09

Experimental method

X-RAY DIFFRACTION (2.04 Å)