[Genetic control of metabolism of mutagenic purine base analogs 6-hydroxylaminopurine and 2-amino-6-hydroxylaminopurine in yeast Saccharomyces cerevisiae].

The influence of inactivation of genes, which control biosynthesis of inosine monophosphate (IMP) de novo and the purine utilization and interconversion pathway, on sensitivity of yeast Saccharomyces cerevisiae cells to the mutagenic and toxic action of 6-hydroxylaminopurine (HAP) and 2-amino-6-hydroxylaminopurine (AHA) was studied. It was shown that the manifestation of HAP and AHA mutagenic properties involves the action of enzyme adenine phosphoribosyltransferase encoded in yeast by APT1 gene. A blockade of each stage of IMP biosynthesis, with the exception of the block mediated by inactivation of genes ADE16 and ADE17 leading to the accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), was shown to enhance yeast cell sensitivity to the HAP mutagenic effect; however, it does not affect the sensitivity to AHA. A blockade of conversion of IMP into adenosine monophosphate (AMP) causes hypersensitivity of yeast cells to the mutagenic action of HAP and to the toxic effect of HAP, AHA, and hypoxanthine. It is fully probable that this enhancement of sensitivity to HAP and AHA is conditioned by changes in the pool of purines. This indicates that genes ADE12, ADE13, AAH1, and HAM1 controlling processes of purine utilization and interconversion in yeast make the greatest contribution to the system of protection against the toxic and mutagenic action of the examined analogs. Possible mechanisms of HAP detoxication in bacteria, yeast, and humans are considered.

[Genetic control of metabolism of a mutagenic analog of 6-N-hydroxylaminopurine bases in Saccharomyces cerevisiae yeasts]. / Izuchenie geneticheskogo kontrolia metabolizma mutagennogo analoga osnovanii 6-N-gidroksilaminopurina u drozhzhei Saccharomyces cerevisiae.

Yeasts were shown to utilize 6-substituted adenine analogues as a purine source via the reutilization pathway leading to the formation of inosine monophosphate (IMP). This occurs because the ade12 strains with blocked conversion of IMP into adenosine monophosphate (AMP) cannot grow on media containing the above analogues as a sole purine source. Haploid strains with the double mutation ham1 ade2 or ham1 ade5 were also incapable of growing on a medium with 6-N-hydroxylaminopurine (HAP) as a sole purine source. However, in this case, this inability was caused by the occurrence of recessive lethal mutations rather than by a defect in purine reutilization. Yeast adenine aminohydrolase (AAH) can deaminate HAP to hypoxanthine. Adenine aminohydrolase (AAH) was uniformly active both in strains with a mutation in the HAMI gene and in strains wild-type with respect to this trait.