CONTROL OF EUCARYOTIC FUNCTION BY METHYLATION

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The objective of this work is to understand the physiological role of several related members of a family of S-adenosylmethionine-dependent methyltransferases in aging, metabolic control, and signal transduction. We will continue our work to characterize the protein L-isoaspartate (D- aspartate) O-methyltransferase that recognizes age-damaged proteins and catalyzes the initial step of a protein repair reaction. Seizures occur as a result of the loss of function of this enzyme in transgenic knockout mice. We will investigate the factors leading to the onset of seizures to help understand the mechanisms involved in human epilepsy and its potential control. We will compare the role of this protein repair enzyme to an enzyme that we have recently discovered (trans-aconitate methyltransferase) that recognizes a spontaneously formed inhibitor of the citric acid cycle in a potential detoxification reaction. We also propose to characterize members of an expanding family of protein arginine methyltransferases. These enzymes interact with signaling molecules such as the interferon receptor, the TIS21 protein and SH3-domain-containing proteins. We will now characterize these gene products to better understand the role of these enzymes in metabolic control, including a novel enzyme we have recently discovered that methylates the delta, or internal guanidino nitrogen atom, or arginine residues. Finally, we will examine the enzymes that catalyze the carboxyl methylation of an elongation factor in protein synthesis that may be regulated by a methylation/demethylation cycle. These enzymes all appear to be members of one revolutionarily related family with a probably common three dimensional structure. While one group of enzymes appears to function in reducing the accumulation of the potentially toxic products generated spontaneously during the aging process, the other group appears to regulate the cell's metabolism and its signal transduction pathways.