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S-Adenosylmethionine:Protein Methyltransferases in Hepatomas¹

Fels Research Institute and Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [W. K. P., S. K., J. E.], and Department of Biochemistry, Cancer Research Unit, College of Medicine, Howard University, Washington, D. C. 20001 [H. P. M.]

Protein methylase III (S-adenosylmethionine:proteinlysine methyltransferase; EC 2.1.1.25) and protein methylase I (S-adenosylmethionine:protein-arginine methyltransferase; EC 2.1.1.23) activities were examined in isolated nuclei and cytosol fraction, respectively, from various hepatomas with different growth rates. The enzyme activities of both enzymes paralleled the rates of tumor growth in fast- and moderately growing hepatomas. The parallelism was more evident with protein methylase I than with protein methylase III. While protein methylase III activity was elevated in the fast- to moderately growing hepatomas, the enzyme that is responsible for demethylating proteins, -alkyllysinase (-alkyl-L-lysine:oxygen oxidoreductase; EC 1.5.3.4), had an inverse relationship to the rate of tumor growth, thus suggesting a possible physiological antagonism. When isolated rat liver nuclei were methylated in vitro with S-adenosyl-L-[methyl-¹⁴C]methionine as methyl donor, H₂SO₄-insoluble protein and histones had almost equal amounts of methyl-¹⁴C incorporated. However, amino acid analysis revealed that methylated arginines are the predominant form of radioactivity in the H₂SO₄-insoluble protein (product of protein methylase I), while methylated lysines are the major methylated amino acids in the histones (product of protein methylase III). Furthermore, the hydrolysate of the H₂SO₄-insoluble protein showed four unknown radioactivity peaks on the amino acid analyzer in addition to the known methylated arginine and lysine derivatives.

¹ This work was supported by Grants AM-09603, CA 10439, CA 12226, and GM 20594 from NIH and Grant 74-BC from the American Cancer Society.

Received 11/11/74. Accepted 1/22/75.