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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM026020-28
Application #
6993657
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ikeda, Richard A
Project Start
1978-12-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
28
Fiscal Year
2006
Total Cost
$581,907
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Clarke, Steven G (2018) The ribosome: A hot spot for the identification of new types of protein methyltransferases. J Biol Chem 293:10438-10446
Hadjikyriacou, Andrea; Clarke, Steven G (2017) Caenorhabditis elegans PRMT-7 and PRMT-9 Are Evolutionarily Conserved Protein Arginine Methyltransferases with Distinct Substrate Specificities. Biochemistry 56:2612-2626
Jain, Kanishk; Warmack, Rebeccah A; Debler, Erik W et al. (2016) Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures. J Biol Chem 291:18299-308
Al-Hadid, Qais; Roy, Kevin; Chanfreau, Guillaume et al. (2016) Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity. RNA 22:489-98
Caslavka Zempel, Katelyn E; Vashisht, Ajay A; Barshop, William D et al. (2016) Determining the Mitochondrial Methyl Proteome in Saccharomyces cerevisiae using Heavy Methyl SILAC. J Proteome Res 15:4436-4451
Lowenson, Jonathan D; Shmanai, Vadim V; Shklyaruck, Denis et al. (2016) Deuteration protects asparagine residues against racemization. Amino Acids 48:2189-96
Al-Hadid, Qais; White, Jonelle; Clarke, Steven (2016) Ribosomal protein methyltransferases in the yeast Saccharomyces cerevisiae: Roles in ribosome biogenesis and translation. Biochem Biophys Res Commun 470:552-557
Debler, Erik W; Jain, Kanishk; Warmack, Rebeccah A et al. (2016) A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase. Proc Natl Acad Sci U S A 113:2068-73
Hadjikyriacou, Andrea; Yang, Yanzhong; Espejo, Alexsandra et al. (2015) Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2. J Biol Chem 290:16723-43
Yang, Yanzhong; Hadjikyriacou, Andrea; Xia, Zheng et al. (2015) PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145. Nat Commun 6:6428

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