Thiamine dependent enzymes

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. 

Butterworth, R. F. and Heroux, M. Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes. /. Neurochem. 52,1079-1084,1989. 

Thiamin-dependent enzymes, ACETOLACTATE SYNTHASE BENZOYLFORMATE DECARBOXYLASE BRANCHED-CHAIN a-KETO ACID DEHYDROGENASE COMPLEX... 

M. Muller, G. A. Sprenger, Thiamine-dependent enzymes as catalysts of C-C-bonding reactions The role of orphan enzymes, in Thiamine Catalytic Mechanisms and Role in Normal and Disease States, Marcel Dekker, New York, 2004, pp. 77-91. 

Structures of Thiamin-Dependent Enzymes 4. The Variety of Enzymatic Reactions Involving Thiamin 5. Oxidative Decarboxylation and 2-Acetylthiamin Diphosphate. 6. Thiamin Coenzymes in Nerve Action 753. .. Table 14-4 Some Pyruvoyl Enzymes... 

The crystal structures of thiamin-dependent enzymes (see next section) as well as modeling102 103 suggest that lactylthiamin pyrophosphate has the conformation shown in Eq. 14-21. If so, it would be formed by the addition of the ylid to the carbonyl of pyruvate in accord with stereoelectronic principles, and the carboxylate group would also be in the correct orientation for elimination to form the enamine in Eq. 14-21, step b.82 83a A transient 380- to 440-nm absorption band arising during the action of pyruvate decarboxylase has been attributed to the enamine. 

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

As an obvious extension of the benzoin reaction, the cross-coupling of aldehydes or of aldehydes and ketones was first achieved with the thiamine-dependent enzyme benzoylformate decarboxylase. This linked a variety of mostly aromatic aldehydes to acetaldehyde to form the corresponding a-hydroxy ketones, both chemo- and stereoselectively [31]. Synthetic thiazolium salts, developed by Stetter and co-workers and similar to thiamine itself [32], have been successfully used by Suzuki et al. for a diastereoselective intramolecular crossed aldehyde-ketone benzoin reaction during the course of an elegant natural product synthesis [33], Stereocontrol was exerted by pre-existing stereocenters in the specific substrates, the catalysts being achiral. 

Malandrinos G., Louloudi, M., Deligiannakis, Y., and Hadjiliadis, N. (2001) Two-dimential hyperfme sublevel correlation spectroscopy applied in the study of a Cu+2-[pentapeptide]hydroxyethyl) thiamin pyrophosphatej-pentapeptide] system as a model of thiamin-dependent enzymes, J. Phys. Chem. B, 105, 7223-7233. 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

Blair PV, Kobayashi R, Edwards HM 3rd, Shay NF, Baker DH, and Harris RA (1999) Dietary thiamin level influences levels of its diphosphate form and thiamin-dependent enzymic activities of rat wer. Journal ofNutrition 129, 641-8. 

Butterworth RF (2006) Metabolic Encephalopathies. In Siegel GJ, Albers RW, Brady ST, Price DL (eds) Basic neurochemistry, 7th edn. Elsevier, London, pp 593-602 Butterworth RF, Besnard AM (1990) Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer s disease. Metab Brain Dis 5(4) 179-184 Butterworth RF, GaudreauC, Vincelette J, Bouigault AM, LamotheF, Nutini AM (1991) Thiamine deficiency and Wernicke s encephalopathy in AIDS. Metab Brain Dis 6(4) 207-212 Butterworth RF, Heroux M (1989) Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes. J Neurochem 52(4) 1079-1084... 

Butterworth RF, Kiil JJ, Harper CG (1993) Thiamine-dependent enzyme changes in the brains of alcoholics relationship to the Wemicke-Korsakoff syndrome. Alcohol Clin and Exp Res 17(5) 1084-1088... 

Hyland S, Muller D, Hayton S, Stoeckhn E, BareUa L (2(X)6) Cortical gene expression in the vitamin E-deficient rat possible mechanisms for the electrophysiological abnormalities of visual and neural function. Ann Nutr Metab 50(5) 433-441 Heroux M, Raghavendra Rao VL, Lavoie J, Richardson JS, Butterworth RF (1996) Alterations of thiamine phosphorylation and of thiamine-dependent enzymes in Alzheimer s disease. Metab Brain Dis ll(l) 81-88... 

Giguere, J.-F., and Butten orth, R. R (1987). Activities of thiamine-dependent enzymes in tw o experimental models of thiamine deficiency encephalopathy. Neurachem. Res. 12, 3i)5-310. 

Yamashita, K., Sasaki, S.-i., Osaki, T., Nango, M., Tsuda, K. A holoenzyme model of thiamine dependent enzyme asymmetrical acyloin condensation using a lipid catalyst in a bilayer membrane. Tetrahedron Lett. 1995, 36, 4817-4820. 

Haake P (1987) Thiamin-dependent enzymes. In Page MI, Williams A (eds) Enzyme Mechanisms. Royal Society of Chemistry, London, p 390... 

Y. Zou, Investigating the Mechanism of Catalysis in Thiamin Dependent Enzymes. Ph.D. Thesis, Rutgers University Graduate Faculty at Newark, NJ, 1999. 

The spectral properties and conformational preferences of some 1 jB -thiadiazole macrocycles have been reported. In connection with thiazoles we find mention of a useful reagent for the spectro-photometric determination of cobalt, 4C labelling of a new B-adrenergic blocking agent, S-596, and synthesis of analogues of the cationic terminus of the antitumour agent Bleomycin A21 . Additionally, a polymer-supported thiazolium salt catalyst, as a model for the thiamine-dependent enzymes, has been prepared, and three 2-alkylbenzothiazole volatile flavour constituents... 

Thiamine models and perspectives on the mechanism of action of thiamine-dependent enzymes 06CSR684. 

D. HUvert, R. Breslow, Functionalized cyclodextrins as holoenzyme mimics of thiamine-dependent enzymes, Bioor. Chem., 1984, 12, 206-220. 

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