Abstract

1. Aminoacylase I (EC 3.5.1.14) is a homodimeric zinc-binding metalloenzyme located in the cytosol. It catalyzes the hydrolysis of N-linked acyl groups in L-amino acids, including N-acetylated derivatives of serine, glutamic acid, alanine, methionine, glycine, leucine, and valine.

   
   

2. Aminoacylase I needs to be differentiated from other acylases with diverse substrate specificities identified in mammalian tissues, including aminoacylase II (aspartoacylase) (EC 3.5.1.15), aryl acylamidase (EC 3.5.1.13), and ε-acyllysine acylase (EC 3.5.1.17).

   
   

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. 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. The first patient reported with aminoacylase I deficiency presented in the neonatal period with signs of an acute encephalopathy such as feeding problems, hypotonia, seizures, and apneic spells. A sensorineural hearing deficit was detected by auditory brain stem response. Cerebral MRI showed abnormal signals in the cortico-subcortical zones consistent with cortical laminar necrosis. The seizures and feeding problems improved after the neonatal period. Cerebral MRI at 4 months of age showed mild signs of cerebral cortical atrophy. At 6 months, psychomotor development was within normal limits and clinical neurologic examination was normal. Four additional patients were reported since then. Their clinical presentation was heterogeneous. One had a mild psychomotor retardation, another a moderate psychomotor retardation combined with a coordination disorder and hypotrophy of the corpus callosum and vermis, delayed myelination of the cerebral white matter, and syringomyelia on MRI. One patient had muscular weakness but a normal cognitive development. The fourth patient was asymptomatic until the age of 17 months. A biotinidase deficiency had been detected by neonatal screening in this patient.

   
   

6. At this moment it is not clear whether the aminoacylase I deficiency represents a true metabolic disorder with a causal relationship between the enzyme defect and the clinical phenotype, or merely a biochemical abnormality.

   
   

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 of 408 amino acids with a predicted molecular mass of 45,882 Da. Mutations have been detected in aminoacylase 1-deficient probands, including an obligatory splice-site allele, a 2-bp insertion, and a missense allele (R353C), the last also found on 5 of 161 and 1 of 210 normal chromosomes in 2 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, mostly by 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.

   
   

9. The intracellular catabolism of N-acetylated proteins is mediated by the ATP-ubiquitin-dependent proteasome (Fig. 1). 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 3.4.19.1) 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.

   
   

Purchase Chapter PDF

Access All of OMMBID

Already a user? Sign in here

Username:

Password:

Forgot your Username/Password?