PMID:21054786

Citation	Welin, M, Egeblad, L, Johansson, A, Stenmark, P, Wang, L, Flodin, S, Nyman, T, Trésaugues, L, Kotenyova, T, Johansson, I, Eriksson, S, Eklund, H and Nordlund, P (2010) Structural and functional studies of the human phosphoribosyltransferase domain containing protein 1. FEBS J. 277:4920-30
Abstract	Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 2.4.2.8) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency (k(cat)/K(m)) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway.
Links	PubMed Online version:10.1111/j.1742-4658.2010.07897.x
Keywords	5'-Guanylic Acid/metabolism; Amino Acid Sequence; Cloning, Molecular; Crystallography, X-Ray; Guanine/metabolism; Humans; Hypoxanthine/metabolism; Hypoxanthine Phosphoribosyltransferase/chemistry; Hypoxanthine Phosphoribosyltransferase/genetics; Hypoxanthine Phosphoribosyltransferase/metabolism; Kinetics; Metabolome; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Structure, Quaternary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Structural Homology, Protein; Substrate Specificity
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PRDC1		GO:0004422: hypoxanthine phosphoribosyltransferase activity	ECO:0000314:		F		Table 2	complete
HUMAN:PRDC1	NOT|involved_in	GO:0046038: GMP catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRDC1	enables	GO:0042803: protein homodimerization activity	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9NRG1	F		Seeded From UniProt	complete
HUMAN:PRDC1	NOT|involved_in	GO:0006178: guanine salvage	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRDC1	NOT|enables	GO:0004422: hypoxanthine phosphoribosyltransferase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:PRDC1	enables	GO:0000287: magnesium ion binding	ECO:0000304: author statement supported by traceable reference used in manual assertion		F		Seeded From UniProt	complete

References

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