Serine hydroxymethyltransferase scheme

Serine hydroxymethyltransferase is a PLP-dependent aldolase. It catalyzes interconversion between glycine and various P-hydroxy-a-amino acids, such as serine and threonine, via formation of a quinoid intermediate derived from PLP with the amino acid substrate (Scheme 2.9). This aldolase-type reaction is of interest as an asymmetric synthesis of a-amino acids via C-C bond formation. 

The glycine-dependent aldolases are pyridoxal 5-phosphate dependent enzymes that catalyze the reversible aldol reaction, where glycine and an acceptor aldehyde form a (i-hydroxy-a-amino acid (Scheme 5.47).74 Serine hydroxymethyltransferases, SHMT (EC 2.1.2.1), and threonine aldolases, two types of glycine dependent aldolases, have been isolated. In... 

A transferase that also has aldolase activity and has been used to prepare a number of chiral compounds is the enzyme serine hydroxymethyltransferase (SHMT) (EC 2.1.2.1). This enzyme, also known as threonine aldolase, catalyzes the physiological reaction of the interconversion of serine and glycine with pyridoxal phosphate (PLP) and tetrahydrofolate (FH4) as the shuttling cofactor of the C-1 unit. It also catalyzes a number of other reactions, some of which are independent of PLP and FH4 [72]. The SHMT-catalyzed aldolase reaction generates two stereocenters, which it does stereospecifically at the (/.-carbon, whereas it is less strict at the [l-carbon (Scheme 13). Nevertheless, this enzyme from porcine liver, Escherichia coU and Candida humicola (threonine aldolase) has been used to prepare a number of P-hydroxy-a-amino acids [73-76],... 

Use of serine hydroxymethyltransferase with [2,2- H2]glycine and or [2,2- H2]glycine and H20 gives (2S)- and (2/ )-[2- H 2- Hj]glycines, respectively, and these were incubated with glycine reductase from Clostridium sticklandii to yield chirally labeled acetates (62) (Scheme 14). These acetates were assayed as described in references 3 and 7 to show that the reduction proceeded with inversion of configuration (62). 

The (3R)- and (3S)-[3- Hi,3- Hi]serines 60, Hj, = H, H = H, and 60, H = H, Hj = H, respectively, were also used with the coupled enzymes serine hydroxymethyltransferase and methylenetetrahydrofolate reductase (EC 1.1.1.171) (100). Enzymic reduction of the labeled samples of the intermediate 5,10-methylenetetrahydrofolic acid 56b gave samples of 5-methyltetrahydrofolic acid 91 (Scheme 26). These were degraded to acetate by a sequence that involved one inversion of configuration, and assay of the acetates showed that the overall stereochemistry of the reduction was as in Scheme 26 (100). 

Deamination of amino acids in animal tissue is generally effected by transamination with an a-keto-acid. In the majority of cases, this is 2-oxoglutarate formed by the citric acid cycle. Aspartate aminotransferase and alanine aminotransferase are examples of this kind of reaction. In Figure 2.7, transamination involving these enzymes is depicted as it is known to occur in mammalian liver. Note that the scheme shown here requires participation of oxalacetate and pyruvate and thus is intimately connected with metabolic pathways considered earlier. Serine and glycine are readily interconvertible in animal tissue by the enzyme serine hydroxymethyltransferase. It is worth noting also that decarboxylation of serine to ethanolamine as mentioned above can be followed by A -methylation to yield choline. Choline is both an essential component of many... 

Threonine aldolases (ThrA EC4.1.2.5) and serine hydroxymethyltransferases (SHMT EC 2.1.2.1) are pyridoxal-5 -phosphate (PEP) dependent aldolases that catalyze the aldol addition of glydne to aldehydes [155-158], Since two new stereogenic centers are formed, four possible stereoisomers can be formally obtained. However, contrary to the case of DHAP-dependent aldolases, the four set of stereocomplementary enzymes have not been found in nature yet (Scheme 10.7) [157,159,160]. 

Glycine (Gly, G) is generated from serine (Ser, S) by the loss of the elements of formaldehyde (CH2O) that is, while it is possible that formaldehyde is actually formed in situ, it is considered unhkely as a free species and so the enzyme catalyzing this process, glycine hydroxymethyltransferase (EC 2.1.2.1), has both pyridoxal and tetrahydrofolate in close proximity in the active site. As shown in Scheme 12.9, pyridoxal-coordinated serine (Ser,S) loses the equivalent of formaldehyde ( CH2O ) to the cofactor tetrahydrofolate to produce 5,10-methylenetetrahydrofolate, a species utilized as a source of methylene units for methylation of other intermediates. 

---