Chapter 18: Disorders of Transsulfuration

INTRODUCTION

Transsulfuration is the major metabolic route for the catabolism of methionine in humans and involves the formation of S-adenosylmethionine (AdoMet), S-adenosylhomocysteine (AdoHcy), homocysteine, cystathionine, and cysteine.^1,2,3 The methionine transamination pathway is also involved in methionine metabolism but is a minor pathway that occurs only when methionine levels are abnormally high (>350 μmol/L),^2,3 and leads to the formation of 4-methylthio-2-oxobutyrate, 3-methylthiopropionate, methanethiol and dimethylsulphide.⁴

Inborn errors of transsulfuration result from mutant alleles leading to severe loss of function of enzymes involved in the conversion of the essential amino acid methionine to cysteine.¹ Cysteine is a key component of the glutathione cycle, linking this cycle to methionine metabolism. Methionine originating from the diet or from protein catabolism undergoes a number of metabolic transformations. Besides its role in protein synthesis, methionine’s major function is the conversion of methionine to AdoMet. AdoMet is the donor of a methyl group (one-carbon unit) in a wide range of vital biological methylation reactions, including the methylation of DNA and RNA, and the formation of neurotransmitters, hormones, creatine, and phospholipids. AdoMet also provides the propylamino group for the synthesis of polyamines, which as polycations are important in the stabilization of intracellular structures containing negatively-charged species, such as negatively-charged DNA, or in membranes. In the polyamine synthesis pathway AdoMet is first decarboxylated by AdoMet decarboxylase and then donates a propylamino group to putrescine, which is formed from ornithine, yielding spermidine and 5-methyl-thioribose 1-phosphate.¹ This latter compound can be reconverted to methionine.

The conversion of the essential amino acid methionine to cysteine (Figure 18-1) begins with the methionine adenosyltransferase (MAT) catalyzed activation with ATP to AdoMet. The donation of the methyl group of AdoMet in any of the many AdoMet-dependent methyl transferase reactions results in the formation of AdoHcy. If excess methionine is present, ad random methylation is prevented via a reaction catalyzed by the highly abundant glycine methyltransferase, which transfers the methyl group to glycine, which is thereby converted to sarcosine (N-methylglycine).⁵ Glycine methyltransferase (GNMT) fulfills the need for a high capacity utilization of AdoMet and can be considered an integral enzyme in the transsulfuration sequence. AdoHcy, through competitive inhibition of many AdoMet dependent methyltransferases, plays a critical role in the regulation of biological methylation. AdoHcy is then hydrolyzed by AdoHcy-hydrolase to adenosine and homocysteine (Hcy).⁶ The equilibrium constant of this reaction strongly favors AdoHcy synthesis, but as long as Hcy and adenosine are efficiently removed, hydrolysis predominates. In the remethylation pathway, Hcy is converted to methionine through either the 5′-methyltetrahydrofolate and cobalamin–dependent reaction catalyzed by methionine synthase (See Chapter 19) or the betaine methyltransferase catalyzed reaction.⁷ Alternatively, Hcy is condensed in transsulfuration with serine by cystathionine β-synthase (CBS) to form cystathionine. CBS is a pyridoxal phosphate (vitamin B₆) requiring enzyme which has an AdoMet-binding activation site, and it also binds heme but the role ...