Threonine synthase reaction

Branched Chain Amino Acid Biosynthesis. The branched chain amino acids, leucine, isoleucine and valine, are produced by similar biosynthetic pathways (Figure 2.11). In one pathway, acetolactate is produced from pyruvate and in the other acetohydroxybutyrate is produced from threonine. Both reactions are catalysed by the same enzyme that is known as both acetolactate synthase (ALS) and acetohy-droxy acid synthase (AHAS). 

Write out an abbreviated reaction sequence for its conversion to L-threonine by the action of threonine synthase. 

Only two enzymes (threonine synthase (TS) and CGS) are known to catalyze the 7-replacement reaction, which is composed of two distinct half-reactions. The mechanism involves the elimination of the 7-leaving group, followed by a Michael addition, where water or cysteine reacts with the /3,7-unsaturated ketimine to form the final product, L-threonine and L-cystathionine, respectively. In the case of TS, the addition is on the /3-carbon. 

The final reaction in the biosynthesis of threonine involves a /8-y rearrangement and the loss of phosphate from O-phosphohomoserine (Fig. 2). Threonine synthases have been isolated from Lemna (Schnyder et al., 1975) radish, sugarbeet (Madison and Thompson, 1975), peas (Schnyder et al., 1975 Thoen et al., 1978b), and barley (Aames, 1978). None of these enzymes has been extensively characterized but a requirement for pyridoxyl-5 -phosphate was demonstrated after partial purification of the barley and pea enzymes. Unlike several other enzymes associated with threonine synthesis, the activity of threonine synthase was not stimulated by monovalent cations. However, all of the plant enzymes are strongly activated by 5-adeno-sylmethionine (Section III,B,5). 

Starting from the building block of L-aspartate, the biosynthesis of L-threonine comprises five successive reactions sequencially catalyzed by aspartate kinase, aspartyl semialdehyde dehydrogenase, homoserine dehydrogenase, homoserine kinase and threonine synthase. 

Michael reactions (nucleophilic addition at double bonds). In elimination-mediated 6-replaceraent (I+II) by plurifunction-al lyases, such as tryptophanase, 6-tyrosinase, threonine synthase, the step in which the cosubstrate s anion (Y ) adds at the 6-C of the A fcaminosubstrate-coenzyme Schiff base is a Michael reaction (nucleophilic addition). Several nuc-... 

During the synthesis of a group of potential threonine synthase inhibitors, Zervosen studied the synthesis of allylic phosphonates through an Arbuzov-type reaction between allylic bromides and trialkyIphosphites (Scheme 4.48) [100]. Trimethylphosphite was nsed as a representative phosphorus nucleophile in this chemistry. Similar to many of the Arbuzov-type reactions, the chemistry was operationally simple and proceeded under solvent-free conditions. Although the temperature of this process was lower than several of the systems described previously, there are still many substrates that will not survive heating to 100 °C for 8h. 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

PLP-dependent enzymes catalyze the following types of reactions (1) loss of the ce-hydrogen as a proton, resulting in racemization (example alanine racemase), cyclization (example aminocyclopropane carboxylate synthase), or j8-elimation/replacement (example serine dehydratase) (2) loss of the a-carboxylate as carbon dioxide (example glutamate decarboxylase) (3) removal/replacement of a group by aldol cleavage (example threonine aldolase and (4) action via ketimine intermediates (example selenocysteine lyase). 

The rather toxic methylglyoxal is formed in many organisms and within human tissues.174 It arises in part as a side reaction of triose phosphate isomerase (Eq. 13-28) and also from oxidation of acetone (Eq. 17-7) or aminoacetone, a metabolite of threonine (Chapter 24).175 In addition, yeast and some bacteria, including E. coli, have a methylglyoxal synthase that converts dihydroxyacetone to methylglyoxal, apparently using a mechanism similar to that of triose phosphate isomerase. It presumably forms enediolate 2 of Eq. 13-26, which eliminates inorganic phosphate to yield methyl-... 

Trapping of the aminoacrylate intermediate in the reactions catalyzed by cystathionine-y-synthase and y-cystathionase produced the same diastereomer of KEDB which was different from the one formed with bacterial L-threonine dehydratase. Unfortunately, this experiment has apparently not been done with threonine synthetase. 

The syntheses of valine, leucine, and isoleucine from pyruvate are illustrated in Figure 14.9. Valine and isoleucine are synthesized in parallel pathways with the same four enzymes. Valine synthesis begins with the condensation of pyruvate with hydroxyethyl-TPP (a decarboxylation product of a pyruvate-thiamine pyrophosphate intermediate) catalyzed by acetohydroxy acid synthase. The a-acetolactate product is then reduced to form a,/3-dihydroxyisovalerate followed by a dehydration to a-ketoisovalerate. Valine is produced in a subsequent transamination reaction. (a-Ketoisovalerate is also a precursor of leucine.) Isoleucine synthesis also involves hydroxyethyl-TPP, which condenses with a-ketobutyrate to form a-aceto-a-hydroxybutyrate. (a-Ketobutyrate is derived from L-threonine in a deamination reaction catalyzed by threonine deaminase.) a,/3-Dihydroxy-/3-methylvalerate, the reduced product of a-aceto-a-hydroxybutyrate, subsequently loses an HzO molecule, thus forming a-keto-/kmethylvalerate. Isoleucine is then produced during a transamination reaction. In the first step of leucine biosynthesis from a-ketoisovalerate, acetyl-CoA donates a two-carbon unit. Leucine is formed after isomerization, reduction, and transamination. 

Pyruvate is an intermediate in the conversion of these amino acids to acetyl-CoA. Note that glycine is also degraded by glycine synthase to form C02, NHJ, and N5,N10-methylene-THF in an NAD+-requiring reaction. In primates most threonine molecules are degraded to propionyl-CoA. 

The a-oxoamine synthases family is a small group of fold-type I enzymes that catalyze Claisen condensations between amino acids and acyl-CoA thioesters (Figure 16). Members of this family are (1) 8-amino-7-oxononanoate (AON) synthase (AONS), which catalyzes the first committed step in the biosynthesis of biotine, (2) 5-aminolevulinate synthase (ALAS), responsible for the condensation between glycine and succinyl-CoA, which yields aminolevulinate, the universal precursor of tetrapyrrolic compounds, (3) serine palmitoyltransferase (SPT), which catalyzes the first reaction in sphingolipids synthesis, and (4) 2-amino-3-ketobutyrate CoA ligase (KBL), involved in the threonine degradation pathway. With the exception of the reaction catalyzed by KLB, all condensation reactions involve a decarboxylase step. 

Two pathways for PLP biosynthesis de novo are known in plant and microorganisms. The first was extensively studied in Escherichia coli. This pathway is articulated in two branches which join in a ring closure reaction catalysed by PNP synthase. One branch started from pyruvate and glycer-aldehyde 3-phosphate and the other from 4-phosphohydroxy-L-threonine (derived from erythrose 4-phosphate). The second route is when PLP is formed from glutamine, either ribose 5-phosphate or ribulose 5-phosphate and either dihydroxyacetone phosphate or glyceraldehyde 3-phosphate by action of the PLP synthase complex (Roje 2007). This pathway was discovered in fungi and it has become clear that it is much more widely distributed than the first pathway. It exists in Archaea, most eubacteria and plants. 

Aspartate 4-semialdehyde, seen, for example, in Scheme 12.13, which provided a pathway for the biosynthesis of the essential amino acid methionine (Met, M) and in Scheme 12.14, which holds a representation of the biosynthesis of threonine (Thr, T), is also a place to begin to describe a pathway to lysine (Lys, K). As shown in Scheme 12.19, aspartate 4-semialdehyde undergoes an aldol-type reaction with pyruvate (CHsCOCO ") in the presence of dihydropicoUnate synthase (EC 4.2.1.52) to produce a series of intermediates that, it is presumed, lead to (5)-23-dihydropyridine-2,6-dicarboxylate. Then, dihydrodipicolinate reductase (EC 1.3.1.26) working with NADPH produces the tetrahydropyridine, (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate.This heterocycle, in the presence of glutamate (Glu, E) and water, is capable of transamination directly to 2-oxoglutarate and (2S, 6S)-2,3-diaminopimelate in the presence of LL-diaminopimelate aminotransferase (EC 2.6.1.83), while the latter, in the presence of the pyridoxal dependent racemase... 

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