Correlation of Isozyme Patterns of S-Adenosylmethionine Synthetase with Fetal Stages and Pathological States of the Liver¹

The liver is the most active organ engaged in S-adenosylmethionine metabolism. S-Adenosylmethionine synthetase isozymes (EC 2.5.1.6) were studied in normal, fetal, and pathological livers including hepatoma to correlate their activities with developmental stages and pathophysiological states of the liver. Three isozymes of S-adenosylmethionine synthetase, namely low, intermediate, and high-K_m, have been identified from adult rat and human livers. The K_m (methionine) are 3.6 μm, 23 μm, and 1.03 mm for the rat liver isozymes and 3.1 μm, 20 μm, and 0.65 mm for the human liver isozymes. The high-K_m isozyme could be distinguished from other isozymes by its dependency on sulfhydryl reagents, activation by dimethyl sulfoxide, and chromatographic behaviors on Sepharose 6B and DEAE-cellulose columns. The activity of the low-K_m isozyme, and to a lesser extent that of the intermediate-K_m isozyme, was greatly enhanced in livers characteristic of rapid growth, such as in fetal, newborn, and regenerating livers. In contrast, the activity of the high-K_m isozyme was undetectable in fetal livers and was greatly reduced during the growth phase of remnant liver following partial hepatectomy. Only the intermediate-K_m isozyme was detectable in rat Novikoff hepatoma, indicating a unique metabolic feature associated with this tumor with respect to isozymes of S-adenosylmethionine synthetase. Such an aberration may have significant bearing on liver neoplasia. Livers of patients who died of hereditary tyrosinemia showed abnormal isozyme patterns of S-adenosylmethionine synthetase. The high-K_m isozyme was either undetectable, thus resembling the fetal pattern, or present in a relatively low amount. It is suggested that abnormal development of S-adenosylmethionine synthetase isozymes may be partly responsible for abnormal methionine metabolism and hepatic dysfunctions often associated with these patients.