Serine hydroxymethyltransferase SHMT

Pyridoxal-P-dependent serine hydroxymethyltransferase (SHMT 5,10-methylene- 

From these results we see that the 2-Hsj atom of glycine is replaced during the SHMT reaction and since L-serine has the (S) absolute configuration, the overall steric course at C is retention (see Fig. 14). A similar retention at C was shown in the interconversion of glycine into allothreonine (threonine). 

A second stereochemical feature of the SHMT reaction to have been studied concerns the stereochemistry of the events which occur at C-3 (C ) of serine or the 

Biellmann and Schuber [59] used [ H]HC02H as a source of the C, unit for the conversion of glycine into serine in rat liver slices. The labelled formate is presumably converted into Af, iV °-[ H]methylenetetrahydrofolate by the sequence shown in Fig. 17 and its labelled methylene group then used to generate (S)-[3- H]serine. The 

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The metabolism of P-hydroxy-a-amino adds involves pyridoxal phosphate-dependent enzymes, dassified as serine hydroxymethyltransferase (SHMT) (EC 2.1.2.1) or threonine aldolases (ThrA L-threonine selective = EC 4.1.2.5, L-aHo-threonine selective = EC 4.1.2.6). Both enzymes catalyze reversible aldol-type deavage reactions yielding glycine (120) and an aldehyde (Eigure 10.45) [192]. 

The pyridoxal-5 -phosphate dependent serine hydroxymethyltransferase (SHMT EC 2.1.2.1) in vivo catalyzes the interconversion of L-serine 158 and glycine 149 by transfer of the /1-carbon of L-serine to tetrahydrofolate (THF) by which the activated formaldehyde is physiologically made available as a C,-pool. The reaction is fully reversible and provides a means for the stereoselective synthesis of 158 in vitro from donor 149 and formaldehyde. Economical yields (88-94%) of L-serine have thus been obtained on a multimolar scale using raw cell extracts of recombinant Klebsiella aerogenes or E. coll in a controlled bioreactor at final product concentrations > 450 gl 1 [461,462], Several SHMTs have been purified and characterized from various organisms including animal tissues [463,464], eucaryotic [465] and procaryotic... 

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],... 

Tetrahydrofolate (Fig. le) and derivatives (Fig. If, g) are the biologically active forms of folate. This cofactor is involved in many, distinct enzymatic reactions, ranging from the amino acid metabolism, such as serine hydroxymethyltransferase (SHMT) (Fig. 5a), to nucleotide biosynthesis, such as thymidylate synthase (TS) (Fig. 5b) and dihydrofolate reductase DHFR (Fig. 5c). These enzymes are targets for anticancer drugs because they participate in the formation of thymidylate, the only nucleotide that cannot be obtained via the salvage reactions (30). Whereas the search for inhibitors of SHTM has only recently... 

Fig. 5. Three-dimensional structure of serine hydroxymethyltransferase (SHMT) with bound PLP and 5-formyltetrahydro folate (102) (a),...

Fig. 13. Reactions catalysed by serine hydroxymethyltransferase (SHMT). It should be noted that the reaction of Eqn. 1 is the only one with an established physiological role.

In the folate cycle, the THF reacts with serine synthetizing N5,io-methylene-THF (5,10-CH2-THF) in a reaction catalysed by serine hydroxymethyltransferase (SHMT). The 5,10-CH2-THF is reduced to 5-CH3-THF by the... 

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]. 

The pyridoxal-5 -phosphate-dependent threonine aldolases (ThrA EC 4.1.2.5) and serine hydroxymethyltransferase (SHMT EC 2.1.2.1) catalyze the aldol addition of glycine to aldehydes with the formation of two new stereogenic centers [15,44,161-163]. Hence, four possible products can be formally obtained from a single aldehyde, depending on the specificity of the threonine aldolase. All glycine aldolases assayed... 

Metabolism of P-hydroxy-a-amino acids involves pyridoxal phosphate-dependent enzymes that catalyze a reversible cleavage to aldehydes (Fig, 31) and glycine (89). The distinction between L-threonine aldolase (ThrA EC 4.1.2.5), L-a//o-threonine aldolase (EC 4.1.2.6), or serine hydroxymethyltransferase (SHMT EC 2.1,2.1) has often been rather vague since many catalysts display only poor capacity for erythro/threo (i.e., 91/90) discrimination [22]. Many enzymes display a broad substrate tolerance for the aldehyde acceptor, notably including variously substituted aliphatic as well as aromatic aldehydes (Fig. 31) however, a,P-unsaturated aldehydes are not accepted. 

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