Glycine consumption and mitochondrial serine hydroxymethyltransferase in cancer cells: the heme connection

Abstract

It was recently discovered that glycine consumption is strongly related to the rate of proliferation across cancer cells. This is very intriguing and raises the question of what is the actual role of this amino acid in cancer metabolism. Cancer cells are greedy for glycine. In particular, the mitochondrial production of glycine seems to be utterly important. Overexpression of mitochondrial serine hydroxymethyltransferase, the enzyme converting l-serine to glycine, assures an adequate supply of glycine to rapidly proliferating cancer cells. In fact, silencing of mitochondrial serine hydroxymethyltransferase was shown to halt cancer cell proliferation. Direct incorporation of glycine carbon atoms into the purine ring has been proposed to be one main reason for the importance of glycine in cancer cell metabolism. We believe that, as far as the importance of glycine in cancer is concerned, a central role of this amino acid, namely its participation to heme biosynthesis, has been neglected. In mitochondria, glycine condenses with succinyl-CoA to form 5-aminolevulinate, the universal precursor of the different forms of heme contained in cytochromes and oxidative phosphorylation complexes. Our hypothesis is that mitochondrial serine hydroxymethyltransferase is fundamental to sustain cancer metabolism since production of glycine fuels heme biosynthesis and therefore oxidative phosphorylation. Respiration of cancer cells may then ultimately rely on endogenous glycine synthesis by mitochondrial serine hydroxymethyltransferase. The link between mitochondrial serine hydroxymethyltransferase activity and heme biosynthesis represents an important and still unexplored aspect of the whole picture of cancer cell metabolism. Our hypothesis might be tested using a combination of metabolic tracing and gene silencing on different cancer cell lines. The experiments should be devised so as to assess the importance of mitochondrial serine hydroxymethyltransferase and the glycine deriving from its reaction as a precursor of heme. If the observed increase of glycine consumption in rapidly proliferating cancer cells has its basis in the need for heme biosynthesis, then mitochondrial serine hydroxymethyltransferase should be considered as a key target for the development of new chemotherapeutic agents.