TY - JOUR
T1 - Selective inhibition of the sperm-specific lactate dehydrogenase isozyme-C4 by N-isopropyl oxamate
AU - Wong, Carlos
AU - Rodríguez-Páez, Lorena
AU - Nogueda, Benjamín
AU - Pérez, Alfredo
AU - Baeza, Isabel
N1 - Funding Information:
This work was partially supported by research grants from the Dirección de Estudios de Posgrado e Investigación del Instituto Politécnico Nacional (DEPI, IPN), México. C.W., L.R.P., B.N. and I.B. are fellows of the COFAA, IPN, and A.P. is a fellow of the PIFI, IPN. We thank professor Kenneth E. Davis Gaines for correction of the manuscript.
PY - 1997/11/14
Y1 - 1997/11/14
N2 - In the present study, we demonstrated that the attachment of the nonpolar isopropylic carbon chain in the nitrogen of oxamate, converted this competitive inhibitor of LDH isozymes into a powerful selective inhibitor of mouse LDH-C4. The comparative study of the inhibitory effect of oxamate and N-isopropyl oxamate on mouse LDH isozymes pointed out that the isopropylic carbon chain conferred upon N-isopropyl oxamate a high affinity for LDH-C4 and a marked decrease in the affinity for the other isozymes since oxamate showed more inhibitory effect on LDH-1 (K(i) = 0.06 mM) and LDH-5 (K(i) = 0.08 mM), and less inhibitory effect on LDH-C4 (K(i) = 0.25 mM). On the other hand, N-isopropyl oxamate showed the highest inhibitory effect on LDH-C4 (K(i) = 0.014 mM) and poor inhibitory effect on LDH-1 (K(i) = 0.4 mM) and LDH-5 (K(i) = 0.8 mM). Apparently, the enzymatic inactivation proceeded through a reversible binding of N-isopropyl oxamate, facilitated by nonpolar interactions with a hydrophobic region present only in the active site of mouse LDH-C4, resulting in a selective inhibition of this isozyme in comparison with the other LDH isozymes. N-isopropyl oxamate was also a powerful competitive inhibitor of LDH-C4 (K(i) = 0.015 mM) compared with oxamate (K(i) = 0.35 mM), using α-ketoisocaproate as a substrate.
AB - In the present study, we demonstrated that the attachment of the nonpolar isopropylic carbon chain in the nitrogen of oxamate, converted this competitive inhibitor of LDH isozymes into a powerful selective inhibitor of mouse LDH-C4. The comparative study of the inhibitory effect of oxamate and N-isopropyl oxamate on mouse LDH isozymes pointed out that the isopropylic carbon chain conferred upon N-isopropyl oxamate a high affinity for LDH-C4 and a marked decrease in the affinity for the other isozymes since oxamate showed more inhibitory effect on LDH-1 (K(i) = 0.06 mM) and LDH-5 (K(i) = 0.08 mM), and less inhibitory effect on LDH-C4 (K(i) = 0.25 mM). On the other hand, N-isopropyl oxamate showed the highest inhibitory effect on LDH-C4 (K(i) = 0.014 mM) and poor inhibitory effect on LDH-1 (K(i) = 0.4 mM) and LDH-5 (K(i) = 0.8 mM). Apparently, the enzymatic inactivation proceeded through a reversible binding of N-isopropyl oxamate, facilitated by nonpolar interactions with a hydrophobic region present only in the active site of mouse LDH-C4, resulting in a selective inhibition of this isozyme in comparison with the other LDH isozymes. N-isopropyl oxamate was also a powerful competitive inhibitor of LDH-C4 (K(i) = 0.015 mM) compared with oxamate (K(i) = 0.35 mM), using α-ketoisocaproate as a substrate.
KW - Hydrophobic interaction
KW - LDH isozyme
KW - LDH(x)
KW - LDH-C4 inhibition
KW - N-Isopropyl oxamate
UR - http://www.scopus.com/inward/record.url?scp=0344542034&partnerID=8YFLogxK
U2 - 10.1016/S0167-4838(97)00090-3
DO - 10.1016/S0167-4838(97)00090-3
M3 - Artículo
SN - 0167-4838
VL - 1343
SP - 16
EP - 22
JO - Biochimica et Biophysica Acta - Protein Structure and Molecular Enzymology
JF - Biochimica et Biophysica Acta - Protein Structure and Molecular Enzymology
IS - 1
ER -