Disease relevance of APEH

• Sequence analyses of the cDNA and several Achromobacter protease I-digested peptides of the purified protein revealed that porcine liver AARE consists of four identical subunits, and each comprising a single chain of 732 amino acids with acetylmethionine at the N-terminus [1].
• Left ventricular regional ischemia resulted in a marked alteration of the activation patterns (a significant decrease in vectorfield- and breakthroughpoint-similarity) which could be significantly inhibited by pretreatment with AAP 10 [2].
• In electrically driven myocardial preparations obtained from chronically methylxanthine-[aminophylline (APH) and 8-phenyltheophylline (8-PT)] or solvent(DMSO)-treated guinea pigs no differences were found in alteration of mechanical activity under hypoxia and reoxygenation [3].

High impact information on APEH

• Single heart beats were analyzed under control conditions and under treatment with AAP 10 or under regional ischemia with or without AAP 10-pretreatment (10(-8) mol/l) [2].
• A new antiarrhythmic peptide, H2N-Gly-Ala-Gly-4 Hyp-Pro-Tyr-CONH2 (AAP 10), was synthetized using the Fmoc-strategy [2].
• In additional experiments, it could be shown that AAP 10 did not alter action potential duration, maximum dU/dt, amplitude or resting membrane potential of isolated guinea pig muscles using a common intracellular action potential recording technique.(ABSTRACT TRUNCATED AT 400 WORDS)[2]
• Besides the ability of porcine intestinal APH to cleave the first peptide bond in N-protected peptides (Km: 0.8 mM), it is worth stressing that the enzyme was also found to efficiently catalyze the hydrolysis of the isopeptide bond in N-epsilon-Ac-L-Met-L-Lys (Km: 0.7-1.1 mM) [4].
• The acylpeptide hydrolase of porcine intestinal mucosa (pi-APH) is a serine peptidase belonging to the prolyl oligopeptidase family [5].

Biological context of APEH

• On basis of the amino acid sequence deduced from the cDNA sequence of porcine liver AARE [Mitta, M. et al. (1989) J. Biochem. 106, 548-555], sequence determination has been achieved by automated Edman degradation of peptides generated by chemical or enzymatic cleavages of the reduced and S-carboxymethylated protein [6].
• Two structural domains were identified based on the three-dimensional model of pi-APH monomer: a beta-propeller fold in the N-terminal sequence (113-455) and an alpha/beta hydrolase fold corresponding to the C-terminal catalytic domain (469-732) [5].
• Complete covalent structure of porcine liver acylamino acid-releasing enzyme and identification of its active site serine residue [6].
• Two overlapping cloned cDNAs encoding the entire amino acid sequences of the subunits of acylamino acid-releasing enzyme (AARE) [EC 3.4.19.1] have been isolated from porcine liver cDNA lambda gt10 cDNA libraries and sequenced [1].

Anatomical context of APEH

• This effect is highly specific, since prostaglandins (PG) and various agonists of gastrointestinal smooth muscle are not, or only weakly antagonized by these four compounds, whereas various compounds, including narcotic analgesics, are inactive versus AAP [7].

Analytical, diagnostic and therapeutic context of APEH

• Analyses (amino acid analysis, sequencing after the treatment with an acylamino-acid-releasing enzyme, and fast atom bombardment mass spectrometry) of these peptides indicated that the amino-terminal structure of this enzyme is acetylAla-Glu-Asp-Leu-Ile-Leu-Glu [8].
• In addition, we found that AAP 10 depressed the increase in ARI-dispersion during the first minutes of ischemia and accelerated normalization of ARI-dispersion during reperfusion [2].

References