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PMID:21054786

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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

Significance

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


See also

References

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