Introduction to Enzyme and Coenzyme Chemistry - E-Library Home

Enzymatic Redox Chemistry 153
(6) Thymine hydroxylase is an a-ketoglutarate-dependent iron(II) dioxygenase
which catalyses three successive oxidations of thymine, as shown below.
(a) Write a mechanism for the Wrst oxidation.
(b) 5-Ethynyluracil is a potent inhibitor of this enzyme. Inactivation results
in covalent modiWcation of the enzyme with a stoichiometry of one
adduct/enzyme sub-unit, and also generates a byproduct 5-carboxyuracil.
Suggest a possible mechanism of inactivation which would account
for these observations.
O
HN
O
N
H
O
HN
O
OH
O CHO
2 , Fe 2+ HN
O 2 , Fe 2+
HN
O 2 , Fe 2+
HN
α-KG
α-KG
O N
α-KG succinate
O N
H
O
H
+ CO 2
O
H*
O H H*
O 2 , Fe 2+
N
H
α-KG
O
1:1 enzyme adduct +
O
HN
N
H
CO 2 H
O
N
H
CO 2 H
Further reading
General
R.H. Abeles, P.A. Frey & W.P. Jencks (1992) Biochemistry. Jones & Bartlett, Boston.
I. Bertini, H.B. Gray, S.J. Lippard, & J.S. Valentine (1994) Bio-inorganic Chemistry.
University Science Books, Mill Valley, California.
C.T. Walsh (1979) Enzymatic Reaction Mechanisms. Freeman, San Francisco.
C.H. Wong & G.M. Whitesides (1994) Applications for Organic Synthesis: Enzymes in
Synthetic Organic Chemistry. Pergamon, Oxford.
NAD-dependent dehydrogenases
J. Everse & N.O. Kaplan (1973) Lactate dehydrogenases: structure and function. Adv.
Enzymol., 37, 61–134.
F.A. Loewus, F.H. Westheimer & B. Vennesland (1953) Enzymatic synthesis of the
enantiomorphs of ethanol-1-d. J. Am. Chem. Soc., 75, 5018-23.
F.H. Westheimer, H.F. Fisher, E.E. Conn & B. Vennesland (1951) The enzymatic
transfer of hydrogen from alcohol to DPN. J. Am. Chem. Soc., 73, 2403.