Enzymes of serine metabolism in normal, developing and neoplastic rat tissues

Abstract

• 1.|The cellular pattern of serine metabolism was conceptualized into four main areas of metabolic sequences: the biosynthesis of serine from intermediates of the glycolytic pathway (the so-called “phosphorylated pathway”); and alternative pathways of serine utilization initiated by serine dehydratase, serine aminotransferase and serine hydroxymethyltransferase.

• 2.|The known regulatory and adaptive properties of the enzymes involved in these pathways were reviewed in detail and key enzymes associated with each pathway (phosphoserine aminotransferase, serine dehydratase, serine aminotransferase, and serine hydroxymethyltransferase, respectively) were selected for further investigation.

• 3.|Tissue distribution studies in the rat revealed that whereas serine dehydratase and serine aminotransferase activities were largely confined to the liver, phosphoserine aminotransferase and serine hydroxymethyltransferase activities were more broadly distributed. In particular in tissues with a high rate of cell turnover, phosphoserine aminotransferase and serine hydroxymethyltransferase activities were coordinately increased. An increase in serine hydroxymethyltransferase activity coincided temporally with the incorporation of [3-¹⁴C]serine and thymidine into DNA in normal human lymphocytes during proliferation after mitogenic stimulation by phytohemagglutinin. The evidence suggested a primarily gluconeogenic role for serine dehydratase and serine aminotransferase. Serine hydroxymethyl-transferase has a role in providing glycine and one-carbon folate co-factors as precursors for nucleotide biosynthesis and in some situations serves to metabolically couple the pathway of serine biosynthesis to utilization for de novo purine and pyrimidine synthesis.

• 4.|Multiple enzymic forms were distinguished for serine dehydratase, serine aminotransferase and serine hydroxymethyltransferase. For serine dehydratase the two cytosolic multiple forms had no apparent functional significance; the multiple forms were catalytically unmodified by conditions promoting phosphorylation-dephosphorylation in vitro. The mitochondrial form of serine aminotransferase showed adaptive responses in gluconcogenic situations, and the hypothesis was proposed that the mitochondrial isoenzyme of serine hydroxymethyltransferase is associated together with serine aminotransferase in a pathway for gluconeogenesis from protein-derived amino acids such as glycine and hydroxyproline.

• 5.|The adaptive behaviour of the enzymes during the neonatal development of rat liver revealed that serine aminotransferase reached a peak in the mid-suckling period at a time when gluconcogenesis is known to be increased. Use of phosphoenolypyruvate carboxykinase inhibitors (mercaptopicolinate or quinolinate) supported a pathway via serine aminotransferase for gluconeogenesis from serine and hydroxyproline at this developmental stage. The concept of the involvement in a carbon salvage pathway to deal with increased body collagen turnover at this time was advanced. The developmental adaptation of serine aminotransferase at birth was shown to involve glucagon, acting via cyclic AMP, and to be dependent on transcriptional gene regulation.

• 6.|Serine dehydratase showed a biphasic developmental pattern, similar to other enzymes involved in amino acid catabolism. The peaks of activity at the early neonatal and weaning developmental stages were shown to involve the joint action of glucagon, acting via cyclic AMP, and corticosteroid hormones. The inductions were dependent, at least initially, on transcriptional gene regulation but the precise mechanistic role of the two classes of hormone has yet to be defined. At both developmental peaks the distribution of serine dehydratase multiple forms was identical, and differential developmental regulation of the forms was not involved in determining the overall pattern of serine dehydratase development.

• 7.|Phosphoserine aminotransferase and cytosolic serine hydroxymethyl-transferase showed similar developmental patterns with a peak of activity in the perinatal period. This coincides with an active period of hepatocyte proliferation and of nucleotide biosynthesis. A further rise of serine hydroxymethyltransferase coinciding with a second postnatal surge of proliferative hepatocellular growth was independent of de novo serine biosynthesis and reflected increased provision of serine from dietary sources.

• 8.|A survey of the key enzymes of serine metabolism in transplantable rat neoplasms revealed that, in general, serine dehydratase and serine aminotransferase were deleted from the cellular repertoire of metabolic capacities. In contrast, phosphoserine aminotransferase and serine hydroxymethyltransferase were selectively retained to varying degrees in neoplastic tissues.

• 9.|The pattern of serine metabolism displayed in normal, developing and neoplastic tissues revealed an integrated, genetically-programmed, response of enzymes of serine biosynthesis and of alternative enzymes of serine utilization. A major role for serine metabolism in cellular proliferation was emphasized by the coordination of serine synthesis from carbohydrate precursors with the biosynthesis of purine and pyrimidine nucleotides through a metabolic coupling via serine hydroxymethyltransferase.