Restricted rotation of the amino group bonded to thiamin and to 2-(1-hydroxyethyl)thiamin and the question of intramolecular amino group catalysis

Zoltewicz, John A.; Baugh, Thomas D.; King, Roy W.

doi:10.1021/jo00418a035

Cited by 5 publications

(1 citation statement)

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“…However, in a less polar solvent like methanol, with triethylamine as a proton acceptor, the pK a rises to 7.3 19 [Hopmann and Brugnoni 19 assigned their first pK a of thiamin (4.8 in water, 7.3 in methanol) to protonation of the 4′-amino group. However, comparison to more recent literature shows that the ring nitrogen N 1′ is protonated first (pK a ) 5 [16][17][18] ) and then the 4′-amino group (pK a < 0 20,21 )]. All three so far known crystal structures of TDP-dependent enzymes (transketolase, 22 pyruvate oxidase, 23 and PDC 12 ) contain a glutamic acid residue forming a hydrogen bond to the ring nitrogen N 1′ .…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Decarboxylase: A Molecular Modeling Study of Pyruvate Decarboxylation and Acyloin Formation

Lobell

Crout

1996

J. Am. Chem. Soc.

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Using crystal structure data for the pyruvate decarboxylase from Saccharomyces uvarum (which is nearly identical with the enzyme from Saccharomyces cerevisiae), molecular modeling studies have been carried out to investigate the mode of action of the enzyme. Each step of the decarboxylation mechanism can be explained by assuming that the 4‘-amino group of thiamin diphosphate (TDP) acts as a general acid and, in its deprotonated form, as a general base. The carboxyl group of Glu 477 plays a key role in both pyruvate decarboxylation and acyloin formation. In the first case it interacts with the carboxylate group of pyruvate to stabilize the incipient dianion formed by attack of the thiazolium carbanion on pyruvate. In the second case, it interacts with the developing alkoxide anion arising from attack on acetaldehyde or benzaldehyde by the carbanion−enamine intermediate. These studies have permitted the assignment of configuration to all of the key intermediates in the catalytic process. Thus the carbanion−enamine intermediate 5 is found to have the E-configuration. The S-configuration is imposed on the 2-(2-hydroxypropionyl)ethyl)thiamin diphosphate intermediate 4 by the chiral conformation induced in the achiral cofactor through its interactions with the protein. The R-configuration is assigned to the 2-(1-hydroxyethyl)thiamin diphosphate intermediate 6 arising through protonation of the carbanion−enamine intermediate 5. The tight stereochemical control observed in acyloin formation from aromatic aldehydes and pyruvate is explained, as is the relaxed stereocontrol in acyloin formation from acetaldehyde and pyruvate.

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