DNA SYNTHESIS FROM THE β-CARBON OF SERINE BY FETAL AND MATURE HUMAN LIVER

Abstract

In human fetal liver we showed: that cystathionase is absent; methyltetrahydrofolate-homocysteine methyltransferase is higher than in mature human liver; and the alternative remethylation pathway, betaine-homocysteine methyltransferase, is lower. In fetal brain the same enzymatic pattern is found, and serine hydroxymethyltransferase, the enzyme which transfers the β-carbon of serine to tetrahydrofolate to form methylenetetrahydrofolate, is also higher than in mature brain. We predicted that the β-carbon of serine was being shunted into de novo synthesis of DNA, via methylene tetrahydrofolate, rather than serine accepting the sulfur of homocysteine to form cysteine. We now show that incorporation of 3-14C-L-serine into DNA is at least 2-fold higher in fetal human liver slices than in mature human liver slices; incorporation into RNA was 10-fold lower than into DNA. These incorporations were not limited by endogenous methionine. These results confirm our hypothesis directly and provide further evidence that in human fetal liver the sulfur of homocysteine is recycled to methionine at the expense of making cyst(e)ine essential, in order to facilitate the biosynthetic reactions (de novo DNA synthesis, polyamine synthesis, lecithin synthesis, protein synthesis) related to that cycle.