Studies on the active site of succinyl-CoA:tetrahydrodipicolinate N-succinyltransferase. Characterization using analogs of tetrahydrodipicolinate.
Cyclic and acyclic analogs of tetrahydrodipicolinate (THDPA) are evaluated in a study of the active site of succinyl-CoA:tetrahydrodipicolinate N-succinyltransferase. In addition to the natural substrate, THDPA, one cyclic and several acyclic compounds are also succinylated. 2-Hydroxytetrahydropyran-2,6-dicarboxylic acid is a potent competitive inhibitor having a Kis of 58 nM. Based on the results of this study, a stereochemical model for the succinylation of THDPA is proposed. The major features of this model are as follows. 1) The succinylase binds THDPA (L-configuration). 2) Hydration of the imine group follows to give 2-hydroxypiperidine-2,6-dicarboxylic acid in which the two carboxyl groups are trans. 3) Succinylation then occurs and the ring opens to give the acyclic product. It is suggested that 2-hydroxytetrahydropyran-2,6-dicarboxylic acid is a transition state analog by virtue of the fact that it structurally resembles the hydrated intermediate.
D A
DA
Berges
W E
WE
DeWolf
G L
GL
Dunn
D J
DJ
Newman
S J
SJ
Schmidt
J J
JJ
Taggart
C
C
Gilvarg
D000214:Acyl Coenzyme A / Q000378:metabolism; D000217:Acyltransferases / Q000378:metabolism*; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007700:Kinetics; D008433:Mathematics; D010867:Pimelic Acids / Q000494:pharmacology; D011487:Protein Conformation; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000494:pharmacology
D000214:Acyl Coenzyme A; D010867:Pimelic Acids; D011725:Pyridines; D013843:Thiazines; C048697:2,3,4,5-tetrahydro-2,6-pyridinedicarboxylic acid; C009845:alpha-aminopimelic acid; C048696:3,4-dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid; C012046:succinyl-coenzyme A; D000217:Acyltransferases; C040777:succinyl-CoA-tetrahydrodipicolinate N-succinyltransferase