Thiamin pyrophosphate structure

Thiamine pyrophosphate (structure 2.51) is another coenzyme that covalently bonds to a substrate and stabilizes a negative charge. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Most coenzymes have aromatic heterocycles as major constituents. While enzymes possess purely protein structures, coenzymes incorporate non-amino acid moieties, most of them aromatic nitrogen het-erocycles. Coenzymes are essential for the redox biochemical transformations, e.g., nicotinamide adenine dinucleotide (NAD, 13) and flavin adenine dinucleotide (FAD, 14) (Scheme 5). Both are hydrogen transporters through their tautomeric forms that allow hydrogen uptake at the termini of the quinon-oid chain. Thiamine pyrophosphate (15) is a coenzyme that assists the decarboxylation of pyruvic acid, a very important biologic reaction (Scheme 6). 

Coenzymes complement the catalytic action of the amino-acid functional groups. They are bound to apoenzymes (apoproteins) either covalently or non-covalently. It is interesting to note that non-covalently-bound coenzymes are polyanions at neutral pH as exemplified by the structures of glutathione (GSH) [17] and thiamine pyrophosphate [18]. Shinkai and Kunitake (1976b, 1977a) demonstrated the efficient binding of glutathione and coenzyme A (a polyphosphate) to cationic micelles and cationic polysoaps. Thus, the combina- ... 

A. Structure of thiamine and its cofactor form, thiamine pyrophosphate. B. Structure of intermediate formed in the reaction catalyzed by pyruvate dehydrogenase. C. Structure of intermediate formed in the reaction catalyzed by a-keto-glutarate dehydrogenase. 

T4 lysozyme 33,497 helix stability of 528, 529 hydrophobic core stability of 533, 544 Tanford j8 value 544, 555, 578, 582-Temperature jump 137, 138, 541 protein folding 593 Terminal transferase 408,410 Ternary complex 120 Tertiary structure 22 Theorell-Chance mechanism 120 Thermodynamic cycles 125-131 acid denaturation 516,517 alchemical steps 129 double mutant cycles 129-131, 594 mutant cycles 129 specificity 381, 383 Thermolysin 22, 30,483-486 Thiamine pyrophosphate 62, 83 - 84 Thionesters 478 Thiol proteases 473,482 TNfn3 domain O-value analysis 594 folding kinetics 552 Torsion angle 16-18 Tbs-L-phenylalanine chloromethyl ketone (TPCK) 278, 475 Transaldolase 79 Tyransducin-o 315-317 Transit time 123-125 Transition state 47-49 definition 55... 

Schellenberger A, Neef H, Golbig R, Hiibner G, Konig S (1990) Mechanistic aspects of thiamine pyrophosphate enzymes via site-directed substitutions of the coenzyme structure. In Bisswanger H, Ullrich H (eds) Biochemistry and physiology of thiamin diphosphate enzymes. VCH, Weinheim, p 3... 

Edwards, T. E., and Ferre-D Amare, A. R. (2006). Crystal structures of the thi-box riboswitch bound to thiamine pyrophosphate analogs reveal adaptive RNA-small molecule recognition. Structure 14, 1459—1468. 

Thore, S., Leibindgut, M., and Ban, N. (2006). Structure of the eukaryotic thiamine pyrophosphate riboswitch with its regulatory ligand. Science 312, 1208-1211. 

I have been pursuing enzyme mimics, artificial enzymes that perform biomimetic chemistry, since starting my independent career in 1956. In the first work [52-59] my co-workers and I studied models for the function of thiamine pyrophosphate 1 as a coenzyme in enzymes such as carboxylase. We discovered the mechanism by which it acts, by forming an anion 2 that we also described as a stabilized carbene, one of its resonance forms. We examined the related anions from imidazolium cations and oxazolium cations, which produce anions 3 and 4 that can also be described as nucleophilic carbenes. We were able to explain the structure-activity relationships in this series, and the reasons why the thiazolium ring is best suited to act as a biological... 

A wide range of soluble redox enzymes contain one or more intrinsic [2Fe-2S]2+ +, [3Fe-4S]+ , or [4Fe S]2+ + clusters that function in electron transport chains to transfer electrons to or from nonheme Fe, Moco/Wco, corrinoid, flavin, thiamine pyrophosphate (TPP), Fe S cluster containing, or NiFe active sites. Many have been structurally and spectroscopically characterized and only a few of the most recent examples of each type are summarized here. Dioxygenases that function in the dihydroxylation of aromatics such as benzene, toluene, benzoate, naphthalene, and phthalate contain a Rieske-type [2Fe-2S] + + cluster that serves as the immediate electron donor to the monomeric nonheme Fe active site see Iron Proteins with Mononuclear Active Sites). The xanthine oxidase family of molybdoenzymes see Molybdenum MPT-containing Enzymes) contain two [2Fe-2S] + + clusters that mediate electron transfer between the Moco active site and the Other soluble molybdoen-... 

It should he noted that no stmcture analysis is available for the radical-containing form in the above enzymes with the exception of one radical-containing form obtained by oxidizing the existing crystals of E. coli R2 by H2O2 (22). It is rare to obtain the crystal structure of a biological radical within its catalytic site, although, indeed, some successes have been accomplished. One such case is the intermediate radical form of hydroxyethylidene-thiamine pyrophosphate (HE-TPP), which is... 

Branched-chain ketoaciduria (commonly known as Maple Syrup Urine Disease MSUD) is another ailment that may be caused by thiamine deficiency. In MSUD, the oxidative decarboxylation of alpha-keto acids derived from, i.e. valine, isoleucine, and leucine, is blocked due to an inadequate supply of the coenzyme thiamine pyrophosphate (TPP). Clinical symptoms of MSUD include mental and physical retardation. Describe briefly the structure of Riboflavin (Vitamin B-2) and its biochemical role. 

The metabolic functions of pantothenic acid in human biochemistry are mediated through the synthesis of CoA. Pantothenic acid is a structural component of CoA. which is necessary for many important metabolic processes. Pantothenic acid is incorporated into CoA by a. series of five enzyme-catalyzed reactions. CoA is involved in the activation of fatty acids before oxidation, which requires ATP to form the respective fatty ocyl-CoA derivatives. Pantothenic acid aI.so participates in fatty acid oxidation in the final step, forming acetyl-CoA. Acetyl-CoA is also formed from pyruvate decarboxylation, in which CoA participates with thiamine pyrophosphate and lipoic acid, two other important coenzymes. Thiamine pyrophosphate is the actual decarboxylating coenzyme that functions with lipoic acid to form acetyidihydrolipoic acid from pyruvate decarboxylation. CoA then accepts the acetyl group from acetyidihydrolipoic acid to form acetyl-CoA. Acetyl-CoA is an acetyl donor in many processes and is the precursor in important biosyntheses (e.g.. those of fatty acids, steroids, porphyrins, and acetylcholine). 

Figure 4-8. The structures of thiamine pyrophosphate (A), biotin (fi), pyridoxal phosphate (Q, and ascorbate (D). Arrows indicate the reactive sites. When an a-keto acid binds to thiamine pyrophosphate, the keto group attaches and the carboxyl group is released as C02.

D. The structure shown is an adenine moiety. It is not present in thiamine pyrophosphate. 

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