Active site generated analogs of reactive intermediates in enzymic reactions. Potent inhibition of pyruvate dehydrogenase by a phosphonate analog of pyruvate

1977 ◽  
Vol 99 (13) ◽  
pp. 4504-4506 ◽  
Author(s):  
Ronald Kluger ◽  
David C. Pike
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site ◽  
Reactive Intermediates ◽  
Potent Inhibition

How an Enzyme Tames Reactive Intermediates:  Positioning of the Active-Site Components of Lysine 2,3-Aminomutase during Enzymatic Turnover As Determined by ENDOR Spectroscopy

2006 ◽  
Vol 128 (31) ◽  
pp. 10145-10154 ◽  
Author(s):  
Nicholas S. Lees ◽  
Dawei Chen ◽  
Charles J. Walsby ◽  
Elham Behshad ◽  
Perry A. Frey ◽  
...  
Keyword(s):  
Active Site ◽  
Reactive Intermediates ◽  
Endor Spectroscopy

Active-site changes in the pyruvate dehydrogenase multienzyme complex E1 apoenzyme component fromEscherichia coliobserved at 2.32 Å resolution

2006 ◽  
Vol 62 (11) ◽  
pp. 1382-1386 ◽  
Author(s):  
Krishnamoorthy Chandrasekhar ◽  
Palaniappa Arjunan ◽  
Martin Sax ◽  
Natalia Nemeria ◽  
Frank Jordan ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site ◽  
Multienzyme Complex

Active-site modification of mammalian pyruvate dehydrogenase by pyridoxal 5'-phosphate

Biochemistry ◽  
1985 ◽  
Vol 24 (25) ◽  
pp. 7187-7191 ◽  
Author(s):  
Larry R. Stepp ◽  
Lester J. Reed
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site

scholarly journals Formation of N-hydroxy-N-arylacetamides from nitroso aromatic compounds by the mammalian pyruvate dehydrogenase complex

1993 ◽  
Vol 290 (3) ◽  
pp. 783-790 ◽  
Author(s):  
T Yoshioka ◽  
T Uematsu
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site ◽  
Aromatic Compounds ◽  
Pyruvate Dehydrogenase Complex ◽  
Catalytic Efficiency ◽  
Nitroso Compounds ◽  
Factors Affecting ◽  
Porcine Heart ◽  
Alkyl Groups ◽  
Dehydrogenase Complex

Bovine, human and porcine heart mitochondria and isolated porcine heart pyruvate dehydrogenase complex (PDHC) pyruvate-dependently form N-hydroxy-N-arylacetamides from nitroso aromatic compounds, including carcinogenic 4-biphenyl and 2-fluorenyl derivatives. The PDHC-catalysed formation of N-hydroxyacetanilide (N-OH-AA) from nitrosobenzene (NOB), through a Ping Pong mechanism, is optimum at pH 6.8 and is accelerated by thiamin pyrophosphate, but is inhibited by thiamin thiazolone pyrophosphate and ATP. Km pyruvate in the reaction is independent of pH over the range tested, whereas KmNOB increases at lower pH, owing to ionization of an active-site functional group of pKa 6.3. The enzymic ionization decreases log (Vmax/KmNOB). Isolated pyruvate dehydrogenase (E1), a constitutive enzyme of PDHC, forms N-OH-AA by itself and has comparable kinetic parameters to those of the PDHC-catalysed N-OH-AA formation. The catalytic efficiency of PDHC in the formation of N-hydroxy-N-arylacylamides, due to the steric limitation of the active site of E1, is lowered both by bulky alkyl groups of alpha-oxo acids and by p-substituents (but not an o-substituent) on nitrosobenzenes. These nitroso compounds serve as electrophiles in the reaction in which the reductive acetylation step is rate-limiting. The reaction mechanism and other factors affecting N-hydroxy-N-arylacylamide formation are discussed.

Arginine-239 in the beta subunit is at or near the active site of bovine pyruvate dehydrogenase

1995 ◽  
Vol 1252 (2) ◽  
pp. 203-208 ◽  
Author(s):  
Devayani Eswaran ◽  
M. Showkat Ali ◽  
Bhami C. Shenoy ◽  
Lioubov G. Korotchkina ◽  
Thomas E. Roche ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Active Site ◽  
Beta Subunit

scholarly journals The nature of chemical innovation: new enzymes by evolution

2015 ◽  
Vol 48 (4) ◽  
pp. 404-410 ◽  
Author(s):  
Frances H. Arnold
Keyword(s):  
Cytochrome P450 ◽  
Active Site ◽  
Reactive Intermediates ◽  
Transfer Reactions ◽  
Amino Acid Substitutions ◽  
Chemical Catalysis ◽  
Nitrene Transfer ◽  
Enzyme Systems ◽  
Natural Enzyme ◽  
And Function

AbstractI describe how we direct the evolution of non-natural enzyme activities, using chemical intuition and information on structure and mechanism to guide us to the most promising reaction/enzyme systems. With synthetic reagents to generate new reactive intermediates and just a few amino acid substitutions to tune the active site, a cytochrome P450 can catalyze a variety of carbene and nitrene transfer reactions. The cyclopropanation, N–H insertion, C–H amination, sulfimidation, and aziridination reactions now demonstrated are all well known in chemical catalysis but have no counterparts in nature. The new enzymes are fully genetically encoded, assemble and function inside of cells, and can be optimized for different substrates, activities, and selectivities. We are learning how to use nature's innovation mechanisms to marry some of the synthetic chemists’ favorite transformations with the exquisite selectivity and tunability of enzymes.

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