Document Detail

Radical triplets and suicide inhibition in reactions of 4-thia-D- and 4-thia-L-lysine with lysine 5,6-aminomutase.
MedLine Citation:
PMID:  19634897     Owner:  NLM     Status:  MEDLINE    
Lysine 5,6-aminomutase (5,6-LAM) catalyzes the interconversions of D- or L-lysine and the corresponding enantiomers of 2,5-diaminohexanoate, as well as the interconversion of L-beta-lysine and l-3,5-diaminohexanoate. The reactions of 5,6-LAM are 5'-deoxyadenosylcobalamin- and pyridoxal-5'-phosphate (PLP)-dependent. Similar to other 5'-deoxyadenosylcobalamin-dependent enzymes, 5,6-LAM is thought to function by a radical mechanism. No free radicals can be detected by electron paramagnetic resonance (EPR) spectroscopy in reactions of 5,6-LAM with D- or L-lysine or with L-beta-lysine. However, the substrate analogues 4-thia-L-lysine and 4-thia-D-lysine undergo early steps in the mechanism to form two radical species that are readily detected by EPR spectroscopy. Cob(II)alamin and 5'-deoxyadenosine derived from 5'-deoxyadenosylcobalamin are also detected. The radicals are proximal to and spin-coupled with low-spin Co(2+) in cob(II)alamin and appear as radical triplets. The radicals are reversibly formed but do not proceed to stable products, so that 4-thia-D- and L-lysine are suicide inhibitors. Inhibition attains equilibrium between the active Michaelis complex and the inhibited radical triplets. The structure of the transient 4-thia-L-lysine radical is analogous to that of the first substrate-related radical in the putative isomerization mechanism. The second, persistent radical is more stable than the transient species and is assigned as a tautomer, in which a C6(H) of the transient radical is transferred to the carboxaldehyde carbon (C4') of PLP. The persistent radical blocks the active site and inhibits the enzyme, but it decomposes very slowly at </=1% of the rate of formation to regenerate the active enzyme. Fundamental differences between reversible suicide inactivation by 4-thia-D- or L-4-lysine and irreversible suicide inactivation by D- or L-lysine are discussed. The observation of the transient radical supports the hypothetical isomerization mechanism.
Kuo-Hsiang Tang; Steven O Mansoorabadi; George H Reed; Perry A Frey
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Biochemistry     Volume:  48     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-08-25     Completed Date:  2009-09-21     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8151-60     Citation Subset:  IM    
Department of Biochemistry, University of Wisconsin-Madison, 1710 University Avenue, Madison, Wisconsin 53726, USA.
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MeSH Terms
Cobamides / chemistry,  metabolism
Cysteine / analogs & derivatives*,  chemistry,  metabolism,  pharmacology
Deoxyadenosines / chemistry,  metabolism
Deuterium Exchange Measurement
Electron Spin Resonance Spectroscopy
Enzyme Inhibitors / chemistry*,  metabolism,  pharmacology*
Free Radicals / chemistry*,  metabolism
Intramolecular Transferases / antagonists & inhibitors*,  chemistry*,  metabolism
Models, Molecular
Porphyromonas gingivalis / enzymology
Protein Conformation
Quantum Theory
Time Factors
Transcobalamins / chemistry,  metabolism
Grant Support
Reg. No./Substance:
0/Cobamides; 0/Deoxyadenosines; 0/Enzyme Inhibitors; 0/Free Radicals; 0/Transcobalamins; 13870-90-1/cobamamide; 2936-69-8/S-2-aminoethyl cysteine; 4754-39-6/5'-deoxyadenosine; 52-90-4/Cysteine; EC 5.4.-/Intramolecular Transferases; EC 5,6-aminomutase

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