PMID- 10037445
OWN - NLM
STAT- MEDLINE
DCOM- 19990304
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 57
IP  - 6
DP  - 1999 Mar 15
TI  - N-domain selectivity of angiotensin I-converting enzyme as assessed by 
      structure-function studies of its highly selective substrate, 
      N-acetyl-seryl-aspartyl-lysyl-proline.
PG  - 611-8
AB  - The physiological functions of angiotensin I-converting enzyme (ACE) are not 
      limited to its cardiovascular role. ACE constantly degrades 
      N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a natural circulating regulator 
      of the hematopoietic stem cell proliferation, and thereby may be involved in 
      hematopoietic stem cell regulation. AcSDKP is hydrolyzed 50-fold faster by the 
      N-domain active site compared to the C-domain active site. The aim of the present 
      study was to investigate which aminoacid residues from AcSDKP are required to 
      ensure N-domain specificity. Several peptides were designed by progressively 
      increasing the length of the peptidic chain from a tripeptide to a pentapeptide. 
      Kinetic studies of the wild-type ACE and of the two ACE mutants containing a 
      single active domain (N- or C-domain) were performed using Bz (benzoyl) 
      Asp-Lys-Pro, benzoyl-glycyl (Bz-Gly)-Asp-Lys-Pro, and Bz-Gly-Ser-Asp-Lys-Pro 
      (with its intermediate product Bz-Gly-Ser-Asp) as substrates. The unexpected 
      importance of an aspartic acid in the P1 position was discovered, as well as the 
      interaction of the P2 and P3 positions in the substrate to increase or decrease 
      N-domain specificity. Substrates longer than five residues may involve 
      interdependence between subsites. Finally, the discovery of highly specific and 
      novel N-domain substrates cannot be predicted from single subsite mapping, but 
      may require other approaches such as combinatorial peptide libraries.
FAU - Michaud, A
AU  - Michaud A
AD  - Institut National de la Sante et de la Recherche Medicale, Unite 36, College de 
      France, Paris.
FAU - Chauvet, M T
AU  - Chauvet MT
FAU - Corvol, P
AU  - Corvol P
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Oligopeptides)
RN  - EC 3.4.15.1 (Peptidyl-Dipeptidase A)
RN  - H041538E9P (goralatide)
SB  - IM
MH  - Binding Sites
MH  - Kinetics
MH  - Oligopeptides/chemistry/*metabolism
MH  - Peptidyl-Dipeptidase A/chemistry/genetics/*metabolism
MH  - Structure-Activity Relationship
MH  - Substrate Specificity
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - S0006-2952(98)00336-0 [pii]
AID - 10.1016/s0006-2952(98)00336-0 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1999 Mar 15;57(6):611-8. doi: 10.1016/s0006-2952(98)00336-0.