Thiamin branched chain amino acids

Insufficient thiamine significantly impairs glucose oxidation, causing highly aerobic tissues, such as brain and cardiac muscle, to fail first. In addition, branched-chain amino acids are sources of energy in brain and muscle. 

As indicated in Fig. 24-17, pyruvate is the starting material for the formation of both l- and D-alanine and also the branched chain amino acids valine, leucine, and isoleucine.339,340 The chemistry of the reactions has been discussed in the sections indicated in the figure. The first step is catalyzed by the thiamin diphosphate-dependent acetohydroxyacid synthase (acetolactate synthase), which joins two molecules of pyruvate or one of pyruvate and one of 2-oxobutyrate (Fig. 24-17 Fig. 14-3).340a b In E. coli there are two isoenzymes encoded by genes ilv B and ilv HI. Both are regulated by feedback inhibition by valine, probably... 

In a rare autosomal recessive condition (discovered in 1954) the urine and perspiration has a maple syrup odor/ High concentrations of the branched-chain 2-oxoacids formed by transamination of valine, leucine, and isoleucine are present, and the odor arises from decomposition products of these acids. The branched-chain amino acids as well as the related alcohols also accumulate in the blood and are found in the urine. The biochemical defect lies in the enzyme catalyzing oxidative decarboxylation of the oxoacids, as is indicated in Fig. 24-18. Insertions, deletions, and substitutions may be present in any of the subunits (Figs. 15-14,15-15). The disease which may affect one person in 200,000, is usually fatal in early childhood if untreated. Children suffer seizures, mental retardation, and coma. They may survive on a low-protein (gelatin) diet supplemented with essential amino acids, but treatment is difficult and a sudden relapse is apt to prove fatal. Some patients respond to administration of thiamin at 20 times the normal daily requirement. The branched-chain oxoacid dehydrogenase from some of these children shows a reduced affinity for the essential coenzyme thiamin diphosphate.d... 

In nature, thiamine pyrophosphate also catalyses reactions of a-keto-acids other than pyruvic acid. One such sequence leads through some remarkable chemistry to the biosynthesis of the branched-chain amino acids valine and isoleucine. 

Degradation of all three branched-chain amino acids begins with a transamination followed by an oxidative decarboxylation catalyzed by the branched-chain a-keto acid dehydrogenase complex. This enzyme, like a-ketoglutarate dehydrogenase, requires thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD+ (Figure 7-11). 

D. Valine, isoleucine, and leucine (the branched-chain amino acids) are transaminated and then oxidized by an a-keto acid dehydrogenase that requires lipoic acid as well as thiamine pyrophosphate, coenzyme A, FAD, and NAD+. Four of the carbons of valine and isoleucine are converted to succinyl CoA. Isoleucine also produces acetyl CoA Leucine is converted to HMG CoA, which is cleaved to acetoacetate and acetyl CoA... 

D. The branched-chain amino acids (valine, isoleucine, and leucine) are transaminated and then oxidatively decarboxylated by an enzyme that requires thiamine, lipoic add, coenzyme A, FAD, and NAD. 

Cornerstones of treatment are dietary restriction of branched-chain amino acids and high dose thiamine, the latter showing responsiveness in cases with mild and/or intermittent presentations. Acute episodes are life threatening and require aggressive treatment peritoneal dialysis may be necessary because renal clearance of the toxic metabolites is poor. ... 

Thiamine pyrophosphate has two important coenzyme roles, both of which focus mostly on carbohydrate metabolism (Figs. 8.26 and 8.27). The active portion of the coen- rae is the thiazole ring. The first step in the oxidative decarboxylation of a-keto acids requires TPP. The two most common examples are pyruvate and a-ketoglutarate, oxidatively decarboxyatedto acetyl CoA and succinyl CoA, respectively. The same reaction is found in the metabolism of the branched-chain amino acids valine, isoleucine, leucine, and methionine. In all cases, TPP is a coenzyme in a mitochondrial multienzyme complex, consisting of TPP, lipoic acid, coenzyme A, FAD, and NAD. Note the number of vitamins required for the oxidative decarboxylation of a-keto acids thiamine (TPP), pantothenic acid (coenzyme A), riboflavin (FAD),and niacin (NAD). 

Overview of the catabolism of branched-chain amino acids. TPP = thiamin pyrophosphate. 

Most of the vitamins and cofactors discussed in previous chapters of the text would be needed during starvation because many of the essential metabolic pathways must continue to operate. Among the most obvious vitamins needed for those pathways are pyri-doxal phosphate (for the transamination of amino acids), niacin and riboflavin (for electron transport), thiamin (for the oxidative decarboxylation of pyruvate, a-ketoglu-tarate, and the branched-chain amino acids), biotin (for the carboxylation of pyruvate), and cobalamin (for the conversion of methylmalonyl Co A to succinyl Co A). 

Biosynthesis In microorganisms and plants from pyruvic acid 2 pyruvate- 2-acetolactic acid (acetolactate synthase, EC 4.1.3.18 coenzyme thiamin(e) diphosphate)- 2,3-dihydroxyisovaleric acid (2-acetolactate mutase, EC 5.4.99.3)- 2-oxoisovaleric acid (dihydroxy acid dehydratase, EC 4.2.1.9). This is finally am-inated by branched chain amino acid aminotransferase (EC 2.6.1.42). 2-Oxoisovaleric acid is also a precursor of Leu. 

The first committed step in the biosynthetic pathway of the branched chain amino acids is catalyzed by the enzyme acetohydroxyacid synthase (AHAS, EC 2.2.1.6), which is also referred to as acetolactate synthase (ALS). As depicted in Fig. 2.1.1, the pathway leading to valine and leucine begins with the condensation of two molecules of pyruvate accompanied by loss of carbon dioxide to give (S)-2-acetolactate. A parallel reaction leading to isoleucine involves the condensation of pyruvate with 2-ketobutyrate to afford (S)-2-aceto-2-hydroxybutyrate after loss of carbon dioxide. Both reactions are catalyzed by AHAS, which requires the cofactors thiamin diphosphate (ThDP) and flavin adenine dinudeotide (FAD). A divalent metal ion, most commonly is also required. Several excellent reviews... 

Thiamin pyrophosphate (or thiamin diphosphate) is a coenzyme involved in (1) the oxidative decarboxylation of pyruvate to acetyl coenzyme A (enzyme pyruvate dehydrogenase), (2) the oxidative decarboxylation of a-ketoglutarate to succinyl coenzyme A (a-ketoglutarate dehydrogenase) in the tricarboxylic add cycle, (3) the pentose phosphate pathway (transketolase) and (4) the synthesis of branched-chain amino acids such as valine (branched-chain ketoacid dehydrogenase) in bacteria, yeasts and plants. 

Thiamine-dependent enzymes are involved in energy production, nucleic acid synthesis and branched-chain amino acid metabolism. 

Navarro, D., Zwingmann, C., and Butterworth, R.F., 2008. Impaired oxidation of branched-chain amino acids in the medial thalamus of thiamine-deficient rats. Metabolic Brain Disease. 23 445 55. 

Thiamin functions as the coenzyme TDP in the metabolism of carbohydrates and branched-chain amino acids (a-keto-isocaproic, a-keto-yS-methyl valeric, and a-keto-isovaleric acids). In association... 

The three branched chain amino acids are normally metabolized as shown in Figure 6.2. Each amino acid is converted to the corresponding Of-keto acid by a transaminase specific for that amino acid. A solitary case of valinaemia is known, caused by lack of valine transaminase [76] the patient is mentally retarded. The three a-keto acids are decarboxylated by two (or possibly three) enzyme systems, one specific for a-keto-isovaleric acid, the other acting on a-keto-isocaproic and Q -keto-j3-methylvaleric acids [77, 78]. The reaction is complex, proceeding in three distinct steps [78] and requiring coenzyme A, thiamine pyrophosphate, lipoic acid and NAD. The end products are the co-enzyme A thio-esters of the branched chain fatty acids. 

The third type of carbon-branched unit is 2-oxoisovalerate, from which valine is formed by transamination. The starting units are two molecules of pyruvate which combine in a thiamin diphosphate-dependent a condensation with decarboxylation. The resulting a-acetolactate contains a branched chain but is quite unsuitable for formation of an a amino acid. A rearrangement moves the methyl group to the (3 position (Fig. 24-17), and elimination of water from the diol forms the enol of the desired a-oxo acid (Fig. 17-19). The precursor of isoleucine is formed in an analogous way by condensation, with decarboxylation of one molecule of pyruvate with one of 2-oxobutyrate. 

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