Thiamin diphosphate TDP

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

The hypE proteins are 302-376 residues long and appear to consist of three domains. Domain 1 shows sequence identity to a domain from phosphoribosyl-aminoimida-zole synthetase which is involved in the fifth step in de novo purine biosynthesis and to a domain in thiamine phosphate kinase which is involved in the synthesis of the cofactor thiamine diphosphate (TDP). TDP is required by enzymes which cleave the bond adjacent to carbonyl groups, e.g. phosphoketolase, transketolase or pyruvate decarboxylase. Domain 2 also shows identity to a domain found in thiamine phosphate kinase. Domain 3 appears to be unique to the HypF proteins. 

Thiamine diphosphate (TDP) is an essential coenzyme in carbohydrate metabolism. TDP-dependent enzymes catalyze carbon-carbon bond-breaking and -forming reactions such as a-keto acid decarboxylations (oxidative and non-oxidative) and condensations, as well as ketol transfers (trans- and phospho-ketolation). Some of these processes are illustrated in Fig. 12. 

A number of lyases are known which, unlike the aldolases, require thiamine diphosphate (TDP) as a cofactor in the transfer of acyl anion equivalents [389-391], but proceed via enolate-type intermediates by a mechanism that resembles the classical benzoin addition. The most important representative is the transketolase (EC 2,2.1.1) [392] which stems from the oxidative pentose... 

More complex iron-sulfur proteins have been described in the literature, where the iron-sulfur center is associated with other prosthetic groups such as flavin, heme, molybdenum, thiamine diphosphate (TDP), selenium and chlorophyll. 

Thiamin diphosphate (TDP) functions as a cofactor to overcome a chemically difficult problem in carbon-carbon formation and cleavage (77). Editor s note Thiamin diphosphate-dependent decarboxylation is discussed in Chapter 6 by O Leary.) The reaction pattern is exemplified by the decarboxylation of pyruvate to give acetaldehyde (or a more oxidized species) and carbon dioxide. In this reaction, the bond that is broken is not inherently activated toward the reaction. The bond that is to be cleaved is between two carbonyl functions. Since these groups are similarly polarized, heterolytic cleavage is not a likely process. Non-enzymically, the direct cleavage of such a bond involves a homolytic (radical) process. 

Figure 2 Schematic representation of the reactions cataiyzed by the pyruvate dehydrogenase compiex. The Ei subunit (pyruvate dehydrogenase) binds thiamine diphosphate (TDP) the E2 subunit (dihydroiipoyi transacetyiase) contains iipoamide the E3 subunit (dihydroiipoyi dehydrogenase) binds fiavin adenine dinucieotide (FAD).

Chemical structure (Figure 6). Pyrimidine and thiazole moiety linked by methylene bridge - phos-phorylated forms thiamine monophosphate (TMP), thiamine diphosphate (TDP), thiamine triphosphate (TTP). 

TMP), thiamine diphosphate (TDP also known as thiamine pyrophosphate, TPP), and thiamine triphosphate (TTP). TDP, the best characterized form, in its role as a eoenzyme for molecules involved in carbohydrate metabolism e.g. transketolase and pyruvate dehydrogenase) is important for energy production and numerous metabolic functions (Lonsdale 2006). 

In brain, four major enzyme systems utilize thiamine in the form of thiamine diphosphate (TDP) as a major cofactor, i.e. a-ketoglutarate dehydrogenase complex (KGDHC), pyruvate dehydrogenase complex, branched-chain a-keto acid dehydrogenase complex (BCKDHQ and transketolase. 

Vitamin Bi, also called thiamine, is required for all tissues and high concentrations are found in skeletal muscle, heart, liver, kidneys and brain. Thiamine diphosphate (TDP) is the active form and it serves as a cofactor for several enzymes involved in carbohydrate catabolism. These enzymes are also important in the biosynthesis of many cellular constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defenses (Ba 2008). Thiamine is considered an anti-stress vitamin because it strengthens the immune system and improves the body s ability to withstand stress conditions (Haas 1988). 

FIGURE 12.3 Structure of two coenzymes involved in the pyruvate dehydrogenase system, (a) Thiamin diphosphate (TDP). (b) Lipoate... 

Beriberi is caused by a deficiency of thiamin (also called thiamine, aneurin(e), and vitamin Bj). Classic overt thiamin deficiency causes cardiovascular, cerebral, and peripheral neurological impairment and lactic acidosis. The disease emerged in epidemic proportions at the end of the nineteenth century in Asian and Southeast Asian countries. Its appearance coincided with the introduction of the roller mills that enabled white rice to be produced at a price that poor people could afford. Unfortunately, milled rice is particularly poor in thiamin thus, for people for whom food was almost entirely rice, there was a high risk of deficiency and mortality from beriberi. Outbreaks of acute cardiac beriberi still occur, but usually among people who live under restricted conditions. The major concern today is subclinical deficiencies in patients with trauma or among the elderly. There is also a particular form of clinical beriberi that occurs in patients who abuse alcohol, known as the Wer-nicke-Korsakoff syndrome. Subclinical deficiency may be revealed by reduced blood and urinary thiamin levels, elevated blood pyruvate/lactate concentrations and a-ketoglutarate activity, and decreased erythrocyte transketolase (ETKL) activity. Currently, the in vitro stimulation of ETKL activity by thiamin diphosphate (TDP) is the most useful functional test of thiamin status where an acute deficiency state may have occurred. The stimulation is measured as the TDP effect. 

Converted from ng/g creatinine using the factor (xO.376). Based on a decrease of 25% in red cell thiamine diphosphate (TDP). 

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