Adenine Nucleotide Biosynthesis in Cardiac Muscle: Regulation and Intervention

Abstract

It is well established that cardiac ATP breaks down when there is a discrepancy between energy production and energy demand. This occurs in situations such as myocardial ischemia or extreme cardiac overload. In those conditions the breakdown of ATP via ADP and AMP proceeds further to adenosine, inosine and hypoxanthine¹. These degradation products are permeable, are washed out from the myocardium and thus are not available for restitution of ATP via the “salvage pathways” during the recovery period. The restitution of ATP is therefore largely dependent on the de novo formation (= biosynthesis) of adenine nucleotides from small molecular precursor substances. In contrast to the salvage pathways, the de novo synthesis of adenine nucleotides can be measured quantitatively. Utilizing 1-¹⁴C-glycine as precursor substance to which rats were usually exposed for 60 min, the total radioactivity of adenine nucleotides was measured and related to the mean specific activity of the tissue glycine precursor pool thus yielding rates of adenine nucleotide biosynthesis². Using this approach, adenine nucleotide synthesis was determined not only in the normal rat heart but also in the myocardium under various pathophysiological conditions such as recovery from oxygen deficiency², cardiac hypertrophy³, and stimulation with catecholamines⁴. In all these situations, myocardial adenine nucleotide biosynthesis turned out to be enhanced quite considerably. As far as the mechanisms for this stimulation is concerned, there are essentially two major possibilities. 1. Regulation via an ATP-dependent feedback mechanism directed at the first and rate-limiting enzyme of adenine nucleotide biosynthesis, 5-phosphoribosyl-1-pyrophosphate amidotransferase (EC 2.4.2.14), 2. availability of 5-phosphoribosyl-1-pyrophosphate.