Disease relevance of ACY1

• ACY1 has been assigned to chromosome 3p21.1, a region reduced to homozygosity in small cell lung cancer (SCLC), and has been reported to exhibit reduced or absent expression in SCLC cell lines and tumors [1].
• Structural studies of lipooligosaccharides from Haemophilus ducreyi ITM 5535, ITM 3147, and a fresh clinical isolate, ACY1: evidence for intrastrain heterogeneity with the production of mutually exclusive sialylated or elongated glycoforms [2].
• We have focused our efforts on an analysis of chromosomal band 3p21.1 since aminoacylase-1 (ACY1), which is localized to this band, has been shown to have lower levels of expression in several small cell and non-small cell lung cancer cell lines [3].
• In EBV transformed lymphoblasts, aminoacylase I activity was deficient [4].
• A Zn(2+)-dependent aminoacylase mediating this cleavage was purified from Corynebacterium striatum Ax20, and the corresponding gene agaA was cloned and heterologously expressed in Escherichia coli [5].

High impact information on ACY1

• The four currently known Ntn hydrolases (glutamine PRPP amidotransferase, penicillin acylase, the 20S proteasome and aspartylglucosaminidase) are encoded as inactive precursors, and are activated by cleavage of the peptide bond preceding the catalytic residue [6].
• The nucleophile is cysteine in GAT, serine in penicillin acylase, and threonine in the proteasome [7].
• The crystal structures of three amidohydrolases have been determined recently: glutamine PRPP amidotransferase (GAT), penicillin acylase, and the proteasome [7].
• We have examined the expression of aminoacylase-1 (ACY-1), encoded by chromosome 3p21, using both an electrophoretic activity assay and a monoclonal antibody-based ELISA [8].
• ACY-1 was undetectable in a significant number of SCLC cell lines (4/29) and tumors (1/8), but not in non-small cell lung cancer (NSCLC) cell lines (0/19) or tumors (0/9), nor in a variety of other human cell lines (0/15) or colon tumors (0/8) [8].

Chemical compound and disease context of ACY1

• The site of reaction of penicillin acylase from Kluyvera citrophila with the potent inhibitor phenylmethanesulphonyl fluoride was investigated by incubating the inactivated enzyme with thioacetic acid to convert the side chain of the putative active-site serine residue to that of cysteine [9].
• Chemical modification of serine at the active site of penicillin acylase from Kluyvera citrophila [9].
• Abnormal expression of sphingomyelin acylase in atopic dermatitis: an etiologic factor for ceramide deficiency [10]?
• Two mutant forms of penicillin acylase from Escherichia coli strains, selected using directed evolution for the ability to use glutaryl-L-leucine for growth [Forney, Wong and Ferber (1989) Appl. Environ. Microbiol. 55, 2550-2555], are changed within one codon, replacing the B-chain residue Phe(B71) with either Cys or Leu [11].
• Starting from a known glutaryl-7-amino cephalosporanic acid acylase as the protein scaffold, an acylase gene optimized for expression in Escherichia coli and for molecular biology manipulations was designed [12].

Biological context of ACY1

• The genes for human aminoacylase-1 (ACY1, N-acylamino acid aminohydrolase, E.C.3.5.1.14), an enzyme in amino acid metabolism, and beta-galactosidase-A (GLB1, E.C.3.2.1.23), deficient in GM1-gangliosidosis, have been assigned to human chromosome 3 [13].
• Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins [14].
• Two human cDNA libraries and one human genomic DNA library were screened with a previously isolated partial ACY1 cDNA to isolate a full-length transcript [1].
• Sequence analysis of clones from each of these libraries resulted in an ACY1 cDNA of 1438 base pairs with an open reading frame of 1224-base pairs coding for a putative protein of 408 amino acids with a predicted molecular mass of 45,882 Da [1].
• The evolutionary conservation of this gene cluster includes three adjacent human shortest regions of overlap (SROs): 3p21.1 (ACY1), 3p21.3-->p21.2 (CACNA1D), and 3p21.3 (ZNF64) [15].

Anatomical context of ACY1

• Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated [14].
• Southern and northern analyses of ACY1 in SCLC cell lines failed to demonstrate any gross abnormalities of the ACY1 structural gene or instances of absent or aberrantly sized mRNA, respectively [1].
• Both ACY1 activity and this restriction fragment have been further demonstrated to be syntenic to distal 3p21.1 through the use of a panel of human-rodent somatic cell hybrids containing fragments of chromosome 3 [16].
• A variety of human tissues, including lung, brain, liver, kidney, heart, adrenal medulla, and erythrocytes have previously been tested for ACY-1 activity and antigen; all but erythrocytes are positive [8].
• A specific bacterial aminoacylase cleaves odorant precursors secreted in the human axilla [5].

Associations of ACY1 with chemical compounds

• Predominately cytosolic proteins such as selenium binding protein, protein disulfide isomerase, aldehyde dehydrogenase, triosephosphate isomerase, and kidney aminoacylase were involved in adduct formation [17].
• The enzyme ACY-1 hydrolyses both acetyl methionine and acetyl glutamate [18].
• Of 12 histidine and 3 cysteine residues, conserved between the proteins from two species, some are anticipated to form the active site of ACY-1 as either catalytic residues or ligands for an essential Zn2+ atom [19].
• Two systems--amino acylase and glucose isomerase--have been demonstrated to be techno-economically feasible [20].
• [Naylor, S.L., Marshall, A., Hensel, C., Martinez, P.F., Holley, B. & Sakaguchi, A.Y. (1989) Genomics 4, 355-361]; the DNF15S2 locus suffers deletions in small cell lung carcinoma associated with a reduction or loss of acylase activity (EC 3.5.1.14) [21].

Other interactions of ACY1

• 1. PCR analysis of somatic cell and radiation hybrids localized ALAS1 to the same distal region of 3p21.1 as the aminoacylase-1 gene [22].
• They differ also from other N-acylamino acid amidohydrolases: aminoacylase (EC 3.5.1.14) and aspartoacylase (EC 3.5.1.15) [23].
• Antioxidant and antimutagenic activity of mannan neoglycoconjugates: mannan-human serum albumin and mannan-penicillin G acylase [24].
• The amino-acid sequence of a peptide resulting from limited proteolysis of the polypeptide chain with proteinase K, which was determined by microsequencing (RHEFHALRAGFALDEGLA), was found to be very similar to the corresponding sequence of porcine kidney acylase I [25].
• Present experiments were performed on unusually tryptophan-rich protein, bacterial penicillin acylase (28 Trp per dimer of 82 kDa) and were aimed to extend these observations [26].

Analytical, diagnostic and therapeutic context of ACY1

• Sequence analysis revealed no homologies to previously reported cDNA or protein sequences and establishes ACY1 as the first member of a new family of zinc-binding enzymes to be so characterized [1].
• The subcellular location of ACY1 has been established as cytosolic by flow cytometry [1].
• Fluorescence in situ hybridization found ACY1 to be located on pig chromosome 13 in the region q21-->q22 [27].
• Structure comparison of the dinuclear zinc center in a mutant of hAcy1 reported here with dizinc centers in related enzymes points to a difference in zinc ligation in the Acy1/M20 family [28].
• In this paper, we investigate the significance of the three dimerization domain residues of human Acy1 His206, Asn263, and Arg276 and, additionally, the nearby Asp274 for catalysis using site-directed mutagenesis [29].

References