Novel Cancer Therapy: Targeting Methionine Metabolism

Abstract

Methionine is an essential amino acid required in larger quantities during development. Albeit considered essential certain amounts of methionine can be synthesized through methionine synthase (MetS) activity from homocysteine using coenzymes methyl‐tetrahydrofolate (vitamin B 9 ) and methylcobalamin (vitamin B 12 ). Homocysteine can be reused to make methionine which is controlled by the levels of methyl‐tetrahydrofolate (vitamin B 9 ) and methylcobalamin (vitamin B 12 ). The other fate of homocysteine in mammals is to be channeled for cysteine synthesis which are controlled by serine, vitamin B 12 , and the activities of cystathionine betasynthase and cystathionine gammalyase. Methionine is activated into s‐adenosylmethionine (SAM) by methionine adenosyltransferase using ATP. Cytoplasmic and Nuclear MAT had been characterized, establishing the specific compartmentalized methylations. In the nucleus RNA, DNA and histones are modified by methylation, limited by SAM. In cytoplasm phosphatidyl choline, epinephrine, carnitine synthesis etc. requires SAM for methylation. In bacteria, methionine is catabolized to methylthiol and deaminated into alpha‐ketobutyrate by methionine gammalyase‐deaminase (MGLD). MGLD is absent in mammals. Molecularly cloned cytoplasmic‐GFP‐MGLD transfected into many cancer cells evinced either moderate cell death/severe aggregation depending on the cell types. With this priori, GFP‐MGLD gene with nuclear localization signal NLS‐GFP‐MGLD) was transfected into Hela, Ad293T, BHK, PC3 and DU145. In conclusion: total (quantitative) and site‐specific (qualitative) methylation pattern/signature is extremely crucial for cell progression that varies among cell types. Specific global methylation patterns/signatures studies are underway.