Mutations in ACY1, the Gene Encoding Aminoacylase 1, Cause a Novel Inborn Error of Metabolism

Abstract

N-terminal acetylation of proteins is a widespread and highly conserved process. 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. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). 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. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses.

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

“…This observation was persistent, being confirmed retrospectively in samples from 5 months of age onwards, and is characteristic of aminoacylase 1 (ACY1) deficiency (Sass et al 2006;Gerlo et al 2006). This represented a second unrelated diagnosis for this patient, independent of her diagnosis of GA3.…”

Study of the expression and function of ACY1 in patients with colorectal cancer

“…Although no previous studies, to the best of our knowledge, have suggested that there is an association between ACY1 expression and the severity of colorectal cancer, the results of the current study demonstrated that the level of ACY1 mRNA and protein is positively associated with the TNM stage of the tumor. Previously, ACY1 has been widely recognized for its catalytic activity in the acylation of N-terminal amino acids (6)(7)(8)(20)(21)(22). ACY1 is widely expressed in different organs and previous studies have shown that in the human digestive tract ACY1 is particularly abundant in epithelial cells, but not in stromal cells (23,24).…”

“…Previous studies indicate that tumor cells of different clinical stages may exhibit different expression levels of certain biomarkers, which could be used as a target for the diagnosis or treatment of the tumor (3)(4)(5). In addition, with ongoing and advancing research into tumor biology, new targets are being identified and studied, including aminoacylase 1 (ACY1) (6).…”

“…ACY1 is a cytosolic enzyme that deacylates the α-acylated amino acid from the N-terminal peptide of intracellular proteins (6). Following this, terminal acetylated proteins are more stable (7)(8)(9).…”

Metabolite Proofreading in Carnosine and Homocarnosine Synthesis

“…In mammals this family comprises at least two other members that do not act on classical peptides: carnosinase (CNDP1), which acts on carnosine and homocarnosine (22), and aminoacylase 1, which deacetylates free N-acetylamino acids (25) to the exception of N-acetyl aspartate. A fourth member, PM20D1 (very distant from PM20D2), has no known function, and the only protein that acts as a true peptidase is CNDP2, which is a cysteinyl-glycine dipeptidase (26) but also acts on various other true dipeptides (22).…”