Structure of human porphobilinogen deaminase at 2.8 Å: the molecular basis of acute intermittent porphyria

Gill, Raj, Kolstoe, Simon E, Mohammed, Fiyaz, Al d-Bass, Abeer, Mosely, Julie E, Sarwar, Mohammed, Cooper, Jonathan B, Wood, Stephen P and Shoolingin-Jordan, Peter M (2009) Structure of human porphobilinogen deaminase at 2.8 Å: the molecular basis of acute intermittent porphyria. Biochemical Journal, 420 (1). pp. 17-25. ISSN 0264-6021

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Abstract

Mutations in the human PBGD (porphobilinogen deaminase) gene cause the inherited defect AIP (acute intermittent porphyria). In the present study we report the structure of the human uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 Å (1 Å=0.1 nm) resolution (Rfactor=0.26, Rfree=0.29). The protein crystallized in space group P21212 with two molecules in the asymmetric unit (a=81.0 Å, b=104.4 Å and c=109.7 Å). Phases were obtained by molecular replacement using the Escherichia coli PBGD structure as a search model. The human enzyme is composed of three domains each of approx. 110 amino acids and possesses a dipyrromethane cofactor at the active site, which is located between domains 1 and 2. An ordered sulfate ion is hydrogen-bonded to Arg26 and Ser28 at the proposed substrate-binding site in domain 1. An insert of 29 amino acid residues, present only in mammalian PBGD enzymes, has been modelled into domain 3 where it extends helix α23 and forms a β-hairpin structure that contributes to a continuous hydrogen-bonding network spanning domains 1 and 3. The structural and functional implications of the R167Q mutation and other mutations that result in AIP are discussed.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Depositing User: Raj Gill
Date Deposited: 09 Jan 2017 13:04
Last Modified: 09 Jan 2017 13:04
URI: http://sro.sussex.ac.uk/id/eprint/66077
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