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M94A3238.TXT
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1994-10-25
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Document 3238
DOCN M94A3238
TI Properties of the enzyme dipeptidyl peptidase IV (DPP IV/CD26) from a
chemical viewpoint.
DT 9412
AU Barth A; Neubert K; Born I; Heins J; Faust J; Rahfeld J; Brandt W;
Hovanessian AG; A.G.M.V. Institute of Biochemistry, University of Halle,
Germany.
SO Int Conf AIDS. 1994 Aug 7-12;10(1):121 (abstract no. PA0103). Unique
Identifier : AIDSLINE ICA10/94369337
AB DPP IV/CD26 hydrolyzes dipeptide units from the N-termini of peptides
and proteins, preferable at the C-terminal side of proline residues. A
substrate is recognized when the N-terminal amino group is protonated
(positive changed). The best substrates are when in the P1-position is a
proline or a alanine residue, whereas the P2-position can be any amino
acyl residue. In a Xaa-Pro-Yaa tripeptide when the Yaa is a proline or a
hydroxyproline residue (P'1-position), then it is not recognized as a
substrate. The stereospecificity in the P1-position is absolute, whereas
that in the P2-position is relative, depending from the amino acid
residue in the P1-position. Molecular modeling studies give insights
into the possible recognition conformation of substrate molecules,
including the distribution of the positive and negative electrostatic
potential on the surface of such molecules, and some hints about the
possible structure of the catalytic center of the enzyme DPP IV/CD26. In
view of this knowledge, it is possible to develop some dipeptides or
amino acid derivatives which are potent reversible inhibitors of the DPP
IV/CD26 activity. A condition for the generation of the inhibitory
potential is the protonisation of the N-terminal amino function, that
means the formation of a positive potential in this area, and in the
meantime suppression of the negative charge (negative potential) on the
C-terminal end of a dipeptide. In agreement with this, the most potent
inhibitor of such class of compounds is isoleucine-pyrrolidide with a
Ki-value of about 10(-7) M at pH 6.3. Since CD26 is the coreceptor of
CD4 which is required for HIV entry into cells, then current work is
directed on the potential inhibitory effect of DPP IV-specific compounds
on the HIV infection.
DE Amino Acid Sequence Antigens, CD/DRUG EFFECTS/PHYSIOLOGY Antigens,
CD4/DRUG EFFECTS/PHYSIOLOGY Antigens, Differentiation,
T-Lymphocyte/DRUG EFFECTS/PHYSIOLOGY Antiviral Agents/*PHARMACOLOGY
Comparative Study Dipeptides/*PHARMACOLOGY Dipeptidyl
Peptidases/*METABOLISM Human HIV/DRUG EFFECTS/*PHYSIOLOGY Models,
Molecular Molecular Sequence Data Oligopeptides/CHEMISTRY/METABOLISM
Protease Inhibitors/*PHARMACOLOGY Protein Conformation Substrate
Specificity MEETING ABSTRACT
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).