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  1. Aminoacylase I (EC is a homodimeric zinc-binding metalloenzyme located in the cytosol involved in the hydrolysis of N-acylated and N-acetylated amino acids, except L-aspartate.

  2. Aminoacylase I needs to be differentiated from other acylases with diverse substrate specificities identified in mammalian tissues, including aminoacylase II (aspartoacylase) (EC, aryl acylamidase (EC, and ε-acyllysine acylase (EC

  3. Aminoacylase II (aspartoacylase) cleaves the N-acetylated derivative of aspartate but no other N-acetyl amino acids. This enzyme is deficient in Canavan disease (Chap. 229). In the affected patients, increased concentrations of N-acetyl-aspartate can be detected in the brain by nuclear magnetic resonance (NMR) spectroscopy. In the cerebral white matter, abnormal signals are seen on magnetic resonance imaging (MRI). The clinical characteristics of patients with aminoacylase II deficiency are different from those seen in patients with aminoacylase I deficiency.

  4. In the urine of the patients with aminoacylase I deficiency, an increased excretion of several N-acetylated amino acids, including the derivatives of serine, glutamic acid, alanine, methionine, glycine, leucine, and valine, can be detected by gas chromatographic-mass spectrometric (GC-MS) and/or MR spectroscopy. Epstein-Barr virus (EBV)-transformed lymphoblasts can be used for measurement of enzyme activity.

  5. Eleven patients have now been reported with aminoacylase I deficiency.The first patient was reported by Van Coster et al. This patient presented in the neonatal period with signs of an acute encephalopathy. Cerebral MRI showed abnormal signals in the cortico-subcortical zones consistent with cortical laminar necrosis. A repeat cerebral MRI at the age of four months showed mild signs of cerebral cortical atrophy. At six months of age, psychomotor development was within normal limits and clinical neurological examination was normal. During the following years, the patient had developed a severe autism spectrum disorder. Ten additional patients have been reported since then (Sass et al. 16, Sass et. 17, Tylki-Szymanska et al. 19, Calvin et al. 2). Their clinical presentation was heterogeneous. Four of the eleven reported patients suffered from an autism spectrum disorder and/or delay in speech and language development, three had moderate to severe developmental delay, and four had normal cognitive development (two of them had neurological complications). Two were reported to be asymptomatic.

  6. At this moment it is not clear whether aminoacylase I deficiency represents a true metabolic disorder with a causal relationship between the enzyme defect and the clinical phenotype, or whether it confers a risk for developmental delay with speech retardation and autism. There is a possibility that it is only an abnormal biochemical finding without any clinical neurological involvement.

  7. Aminoacylase I is encoded by ACY1, an evolutionarily conserved gene located on the short arm of chromosome 3 (3p21.1). It has an open reading frame of 1224 bp coding for a protein 408 amino acids long with a predicted molecular mass of 45,882 Da. Different mutations have been detected in aminoacylase 1-deficient probands. The missense allele (R353C) is the most common mutation. This mutation was also found on five of 161 and one of 210 normal chromosomes in two different studies.

  8. N-terminal blocking of proteins is a widespread phenomenon in eukaryotic cells. Approximately 50 to 80% of all cellular proteins have a blocked amino terminus, primarily through acetylation of the terminal amino group. Proteins involved are structural proteins (keratins, actins, tropomyosins, crystallins, myelin proteins, ribosomal proteins), as well as enzymes, transfer proteins, and Ca2+- and metal-binding proteins and hormones. The intracellular catabolism of N-acetylated proteins is mediated by the ATP-ubiquitin-dependent proteasome. This large complex degrades N-acetylated proteins into peptides 5 to 30 amino residues long. Among the peptides released from the proteasome are those derived from the N-terminus. These peptides have an N-acetyl-blocked amino-terminus and are first cleaved by acylpeptide hydrolase (EC with the release of the N-acetylated amino acid. In a next step, aminoacylase I hydrolyzes the N-acetylated amino acid to acetate and its free amino acid.

  9. Aminoacylase I possesses important other functions in addition to its role in degradation of N-acetylated proteins. It degrades a range of acyl amino acids with a general preference for straight-chain acyl moieties. In addition, aminoacylase I functions as a tumor suppressor gene in small cell lung cancer and in renal carcinoma, and its expression is dysregulated in neuroblastoma tumors. In one study, aminoacylase I was shown to influence the cellular localization and activity of sphingosine kinase 1, an enzyme that phosphorylates sphingosine to sphingosine-1-phosphate. The latter is a bioactive lipid promoting cell survival, proliferation and migration. Aminoacylase I may also play a role in monitoring responses to oxidative stress and in regulation of cellular redox status.

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