Glycine hydroxymethyltransferase

This pyridoxal-phosphate-dependent enzyme [EC 2.1.2.1], which has a recommended EC name of glycine hydroxymethyltransferase, catalyzes the reversible reaction of 5,10-methylenetetrahydrofolate with glycine and water to produce tetrahydrofolate and L-serine. The enzyme will also catalyze the reaction of glycine with acetaldehyde to form L-threonine as well as with 4-tri-methylammoniobutanal to form 3-hydioxy-N, N, N -trimethyl-L-lysine. 

Biosynthesis of carnitine. v-Butyrobetaine, 2-oxoglutarate dioxygenase (EC 1.14.11.1) occurs in liver, kidney and brain, whereas the other enzymes occur in most tissues. The aldolase cleaving 3-hydroxy-NMrimethyl-L-lysine may be identical with glycine hydroxymethyltransferase (EC 2.1.2.1). (W. A. Dunn etal. J. Biol. Chem. 259(1984) 10764-107701... 

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. 

L-serine glycine + formaldehyde serine hydroxymethyltransferase E. coli 201... 

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]. 

Serine. Following conversion to glycine, catalyzed by serine hydroxymethyltransferase (Figure 30—5), serine catabolism merges with that of glycine (Figure 30-6). 

Figure 30-5. Interconversion of serine and glycine catalyzed by serine hydroxymethyltransferase. (H4 folate, tetrahydrofolate.)...

Daly, E. C. Aprison, M. H. (1974). Distribution of serine hydroxymethyltransferase and glycine transaminase in several areas of the central nervous system of the rat. J. Neurochem. 22, 877-85. 

FIGURE 40-3 Glycine cleavage system and some related reactions. Glycine and serine are readily interchangeable. Enzymes (1) Glycine cleavage system (2) and (4) Serine hydroxymethyltransferase (3) N5 10-methylenetetrahydrolate reductase. N5 I0-CH2-FH4, N5>10-methylenetetrahydrolate FH4, tetrahydrofolic acid. 

In the laboratory, serine hydroxymethyltransferase will catalyze the conversion of threonine to glycine and acetaldehyde in one step, but this is not a significant pathway for threonine degradation in mammals. 

The enzyme serine hydroxymethyltransferase requires pyridoxal phosphate as cofactor. Propose a mechanism for the reaction catalyzed by this enzyme, in the direction of serine degradation (glycine production). (Hint See Figs 18-19 and 18-20b.)... 

Side chain cleavage (Group c). In a third type of reaction the side chain of the Schiff base of Fig. 14-5 undergoes aldol cleavage. Conversely, a side chain can be added by (3 condensation. The best known enzyme of this group is serine hydroxymethyltransferase, which converts serine to glycine and formaldehyde.211-21313 The latter is not released in a free form but is transferred by the same enzyme specifically to tetrahydrofolic acid (Eq. 14-30), with which it forms a cyclic adduct. 

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... 

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. 

Serine is formed from 3-phosphoglycerate (Fig. 15-3). Serine is also synthesized from glycine in a reaction catalyzed by serine hydroxymethyltransferase ... 

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... 

When the glycine formed by serine hydroxymethyltransferase is not required for purine synthesis, it undergoes cleavage to carbon dioxide and ammonium, catalyzed by the glycine cleavage system. This is a multienzyme... 

Serine Hydroxymethyltransferase Serinehydroxymethyltrans-ferase is a pyridoxed phosphate-dependent aldolase that catalyzes the cleavage of serine to glycine and methylene-tetrahydrofolate (as shown in Figure 10.5). Serine is the major source of one-carbon substituted folates for biosynthetic reactions. At times of increeised cell proliferation, the activities of serine hydroxymethyltransferase emd the enzymes of the serine biosynthetic pathway cue increased. The other product of the reaction, glycine, is also required in increased cimounts under these conditions (for de novo synthesis of purines). 

Figure 10.5. Reactions of serine hydroxymethyltransferase (EC 2.1.2.1) and the glycine cleavage system (EC 2.1.2.10). THE, tetrahydrofolate.

C((x)-C(p) bond cleavage in a-amino acids is precedented by the PLP-containing enzyme serine hydroxymethyltransferase, interconverting serine with glycine and a formaldehyde equivalent, but in that case C-C bond cleavage is a retro aldol process This route is not obviously open to ACPC (9). 

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