Pharmacogenetics of cyclic guanylate, antioxidants, and antioxidant enzymes in Neurospora

Previous studies indicate that antioxidant enzyme regulatory gene mutants (Age-) of Neurospora are defective in cellular longevity and development, numerous antioxienzymes, and cAMP, and that dietary cGMP confers normal longevity. Here it is shown that cGMP also phenotypically cures the developmental and enzymatic defects. At least 5 of the 12 known antioxidant enzyme deficiencies are normalized by cGMP.cGMP-mediated enzyme induction apparently requires gene transcription: actinomycin D is inhibitory. The mutants' inferior growth and development are stimulated by feeding cGMP, the cyclic nucleotide phosphodiesterase inhibitor theophylline, antioxidant enzymes, and antioxidants or by omission of both ferrous and cupric ions normally added to the culture medium. The analysis indicates that the inferior growth and development probably is a consequence of the formation of toxic hydroxyl radicals. The mutants are rather specific, conditional cGMP auxotrophs and respond to physiological concentrations of that nucleotide: cAMP tends to be ineffective. The observations indicate that: i) genetic regulation of antioxidant enzymes is a determinant of not only cellular longevity, but also normal growth and development; and ii) the enzymes do indeed provide defense against free radical/oxidant toxicity. The hypothesis that cGMP is a second messenger in regulation of the expression of antioxidant enzyme genes is consistent with experimental data, but remains to be verified.