Human hypoxanthine (guanine) phosphoribosyltransferase: an amino acid substitution in a mutant form of the enzyme isolated from a patient with gout.

We have investigated the molecular basis for a deficiency of the enzyme hypoxanthine (guanine) phosphoribosyltransferase (HPRT; IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) in a patient with a severe form of gout. We reported in previous studies the isolation of a unique structural variant of HPRT from this patient's erythrocytes and cultured lymphoblasts. This enzyme variant, which is called HPRTLondon, is characterized by a decreased concentration of HPRT protein in erythrocytes and lymphoblasts, a normal Vmax, a 5-fold increased Km for hypoxanthine, a normal isoelectric point, and an apparently smaller subunit molecular weight. Comparative peptide mapping experiments revealed a single abnormal tryptic peptide in HPRTLondon. Edman degradation of the aberrant peptide from HPRTLondon identified a serine-to-leucine amino acid substitution at position 109. This substitution can be explained by a single nucleotide change in the codon for serine-109 (UCA leads to UUA). Thus a mutation at the HPRT locus has now been defined at the molecular level.