Genetic relationship between acylpeptide hydrolase and acylase, two hydrolytic enzymes with similar binding but different catalytic specificities.

Abstract

An 87% identity has been found between the reported cDNA sequence that encodes acylpeptide hydrolase (EC 3.4.19.1) [Mitta, M., Asada, K., Uchimura, Y., Kimizuka, F., Kato, I., Sakiyama, F. & Tsunasawa, S. (1989) J. Biochem. 106, 548-551] and a cDNA transcribed from a locus (DNFISS2) on the short arm ofhuman chromosome 3, reported by Naylor et al. [Naylor, S. L., Marshall, A., Hensel, C., Martinez, P. F., Holley, B. & Sakaguchi, A. Y. (1989) Genomics 4,[355][356][357][358][359][360][361]; the DNF15S2 locus suffers deletions in small cell lung carcinoma associated with a reduction or loss of acylase activity (EC 3.5.1.14). Acylpeptide hydrolase catalyzes the hydrolysis of the terminal acetylated amino acid preferentially from small acetylated peptides. The acetylamino acid formed by acylpeptide hydrolase is further processed to acetate and a free amino acid by an acylase. The substrates for the acylpeptide hydrolase and the acylase behave in a reciprocal manner since acylpeptide hydrolase binds but does not process acetylamino acids and the acylase binds acetylpeptides but does not hydrolyze them; however, the two enzymes share the same specificity for the acyl group. These findings indicate some common functional features in the protein structures of these two enzymes. Since the gene coding for acylpeptide hydrolase is within the same region of human chromosome 3 (3p2l) that codes for the acylase and deletions at this locus are also associated with a decrease in acylase activity, there is a close genetic relationship between the two enzymes. There could also be a relationship between the expression of these two enzymes and acetylated peptide growth factors in some carcinomas.The various types of exopeptidases that act on the free NH2-terminal residues of polypeptides have been described in detail (1). The properties of a purified enzyme that cleaves an acetylated terminal amino acid from acetylated peptides (N-acylaminoacylpeptide hydrolase, EC 3.4.19.1, referred to here as acylpeptide hydrolase) have also been reported (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). For example, this enzyme catalyzes the hydrolysis of acetyltrialanine (Ac-Ala3-OH) to acetylalanine (Ac-Ala-OH) and dialanine (Ala2-OH). We reported that the rates of hydrolysis of different blocked peptide substrates varied considerably, depending on the nature of the first and second amino acids. Thus, there was a preference for Ac-Ala-, Ac-Met-, and Ac-Ser-at the blocked terminus (4). Comparison ofthis specificity with the sequences ofabout 100 known proteins acetylated at their NH2-terminal residues indicated that most of them began with Ac-Ala-, Ac-Met-, or Ac-Ser-(13). Furthermore, in these blocked proteins there was a preponderance of charged amino acid residues at the second position. Hence, the characteristics of the terminal sequence of these blocked proteins appear to resemble the substrate specificity ofthe acylpeptide hydrolase. The enzyme displays a broad spectrum with respect to the blocking group, since acetyl, chloroacetyl, formyl,...

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