Polyamine Biosynthesis And Function

Diabetes, Digestive, Kidney Diseases

Investigators

Linked publications & trials

Abstract

The polyamines, putrescine, spermidine, and spermine, are major polybasic compounds in all living cells. These amines are important for many systems related to growth and differentiation. For many years we have been studying how these polyamines are synthesized, how their biosynthesis and degradation are regulated, their physiologic functions, how they act in vivo, and the structure of the various biosynthetic enzymes. For this purpose we have constructed null mutants in each of the biosynthetic steps in both Escherichia coli and Saccharomyces cerevisiae, and have prepared overexpression systems for the biosynthetic enzymes. Our overall studies have aimed at the use of these mutants plus those of S. pombe to elucidate the physiological functions of the polyamines, and, in particular, to ascertain the physiological effects of polyamine deprivation. Our most recent studies have concentrated on the role of methylthioadenosine in the regulation of ornithine decarboxylase and of polyamine biosynthesis in yeast. Methylthioadenosine is a byproduct of the biosynthesis of spermidine and spermine, and is then converted by the ?methionine salvage? pathway to adenine and methionine. The first enzyme in this pathway is methylthioadenosine phosphorylase, and is coded by the MEU1 gene. This gene is of particular interest since it is missing in many tumors. We have studied the role of this gene in controlling polyamine levels, and have clarified conflicting reports in the literature on the mechanisms involved. We have found that methylthioadenosine accumulates in the meu1 deleted mutants, and inhibits spermidine synthase, resulting in decreased spermidine levels. Most of the accumulated methylthioadenosine is excreted into the culture medium During the year we have also completed our work on the role of polyamines in protecting cells from the toxic effects of oxygen . In other studies underway we are continuing our studies, using microarray techniques, on which systems are most affected by the addition of spermidine to polyamine-deficient S. cerevisiae mutants.