The molecular basis of aminoacylase 1 deficiency

Sommer, Anke; Christensen, Ernst; Schwenger, Susanne; Seul, R.; Haas, Dorothea; Olbrich, Heike; Omran, Heymut; Sass, Jörn Oliver

doi:10.1016/j.bbadis.2011.03.005

Cited by 30 publications

(28 citation statements)

References 21 publications

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“…The second mutation (c.574_575insG/p.Ser192Arg fs*64) is novel and resulted in very low levels of ACY1 protein, as shown by immunoblot and immunocytochemistry. This finding is supported by expression studies on transfected cells with Glu233Asp mutation, in which the enzymatic activity was completely loss (Sommer et al 2011). Both mutations identified in our patient involve evolutionary conserved amino acids and are localized in the protein dimerization domain.…”

Section: Discussionsupporting

confidence: 81%

Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

et al. 2014

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Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism presenting with heterogeneous neurological symptoms such as psychomotor delay, seizures, intellectual disability and it is characterized by increased urinary excretion of N-acetylated amino acids. We report on a new patient who presented ACY1 deficiency in association with isolated mild intellectual disability, but neither neurological symptoms nor autistic features. The child showed a compound heterozygous mutation (p.Glu233Asp) and a novel p.Ser192Arg fs*64, predicting an unstable transcript and resulting in very low protein levels.This new ACY1 deficient child was identified through regular screening for inborn error of metabolism adopted in our department in all cases of intellectual disability. This report supports a recommendation to perform metabolic investigations in patients with isolated mild intellectual disability.

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Section: Discussionsupporting

confidence: 81%

Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

et al. 2014

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“…However, little is known about the mechanisms underlying this function. It has been noted that Sphingosine kinase type 1 (SphK1), an anti-apoptosis protein can bind to ACY1 and enhance its anti-apoptotic effect (23,26). However, this alone is not sufficient evidence to demonstrate the function of ACY1 in cancer.…”

Section: Discussionmentioning

confidence: 89%

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

Liu

Cao

et al. 2017

Oncology Letters

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Abstract. Aminoacylase 1 (ACY1) is important for regulating the proliferation of numerous types of cancer. However, the expression and mechanisms underlying the function of ACY1 in colorectal cancer remain unclear. In order to investigate the expression and function of ACY1 in colorectal cancer, tumor tissue and blood samples were collected for analysis from 132 patients diagnosed with colorectal cancer. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting identified significantly increased expression of ACY1 mRNA in colorectal tumor tissue (P<0.05 vs. adjacent normal tissue) and notably increased ACY1 protein levels. This ACY1 mRNA expression was found to be positively correlated with tumor stage. In addition, plasma ACY1 concentration was increased in patients with colorectal cancer compared with healthy controls. Furthermore, in vitro knockdown of ACY1 in human colorectal cancer HT-29 cells was shown to inhibit proliferation and increase apoptosis. This effect was found to be associated with the activation of ERK1 and TGF-β1 signaling. In conclusion, the results of the present study suggest that ACY1 promotes tumor progression, and thus may be a potential target for the diagnosis and treatment of colorectal cancer. IntroductionColorectal cancer, the third most common cancer worldwide, is a major public health issue in China and globally (1). Although advances have been made in surgical and medical treatments, ~40% of patients with colorectal cancer succumb to the cancer (2). The early diagnosis and assessment of tumors is an area of intense study; however, it is a complex issue. 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 (3-5). 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 (7-9). In addition to its function in scavenging N-acylated amino acids, ACY1 has been studied in a number of types of human cancer. In small cell lung cancer (SCLC), renal cell carcinoma and liver cancer ACY1 expression has been demonstrated to be significantly reduced (10-13), suggesting that ACY1 serves a role in inhibiting tumorigenesis. Limited studies have investigated the detailed function and mechanism of ACY1 in tumor proliferation, and certain previous studies have reported that activation of ERK 1/2 and expression of TGF-β may be implicated in this process (13-16). However, the role of ACY1 in gastrointestinal cancer remains unclear. In the present study, the function and regulation of ACY1 in colorectal cancer was investigated through analyzing clinical samples. Materials and methodsPatients and clinical specimens. In total, 160 patients ...

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“…The accumulation of these N-acetylated amino acids has been associated with inherited pathology that results in neurological damage manifested as seizures, mild mental retardation or autism. Their accumulation in urine results from a deficiency of aminoacylase 1, a kidney enzyme that catabolizes free N-acetylated amino acids into acetic acid and the free amino acid (37). In contrast, the N-acetylated amino acids that accumulate in hibernators differ markedly; only methionine occurs in both lists.…”

Section: Discussionmentioning

confidence: 97%

Metabolic cycles in a circannual hibernator

Epperson¹,

Karimpour-Fard

Hunter

et al. 2011

Physiological Genomics

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nation as manifested in ground squirrels is arguably the most plastic and extreme of physiological phenotypes in mammals. Homeostasis is challenged by prolonged fasting accompanied by heterothermy, yet must be facilitated for survival. We performed LC and GC-MS metabolomic profiling of plasma samples taken reproducibly during seven natural stages of the hibernator's year, three in summer and four in winter (each n Ն 5), employing a nontargeted approach to define the metabolite shifts associated with the phenotype. We quantified 231 named metabolites; 106 of these altered significantly, demarcating a cycle within a cycle where torpor-arousal cycles recur during the winter portion of the seasonal cycle. A number of robust hibernation biomarkers that alter with season and winter stage are identified, including specific free fatty acids, antioxidants, and previously unpublished modified amino acids that are likely to be associated with the fasting state. The major pattern in metabolite levels is one of either depletion or accrual during torpor, followed by reversal to an apparent homeostatic level by interbout arousal. This finding provides new data that strongly support the predictions of a long-standing hypothesis that periodic arousals are necessary to restore metabolic homeostasis. Ictidomys tridecemlineatus; Spermophilus; ␥-glutamyl; biliverdin; NacetylA YEAR IN THE LIFE OF A HIBERNATOR begins with reproduction in spring, followed by growth in summer, and then massive storage of fat as fall approaches. Hibernation, characterized by months of fasting and dramatic oscillations between states of cold and warm body temperature (T b ), ensues only after adequate fat stores are deposited (7). Most of the fall and winter months are spent in a state of deep torpor in which metabolic, heart, and respiratory rates are reduced to Ͻ5% of their summer equivalents, and body temperature declines to as low as 0°C, or even below (5). However, all hibernating mammals spontaneously reverse torpor at regular intervals by elevating metabolic rate and employing strictly endogenous mechanisms of heat production including shivering and nonshivering thermogenesis. In the thirteen-lined ground squirrel, Ictidomys tridecemlineatus, elevated metabolic rate and T b (ϳ37°C) are maintained in each interbout arousal for ϳ10 -12 h before dropping again to initiate the next ϳ2 wk bout of torpor. Thus, the circannual hibernation rhythm can be viewed as a cycle between summer homeothermy and winter heterothermy, the latter of which is itself a cycle between torpor and arousal (see Fig. 1). These dramatic physiological shifts of hibernation have been postulated to result from intrinsic metabolic cycles (41) that may be revealed by metabolic profiling (42).Previous work to measure metabolite changes in hibernators documents a number of alterations in liver (2, 32, 36), brain (21, 40), brown adipose tissue (13), bile (4), and blood (1, 9, 24, 31) that begin to assess the metabolites cycling in association with hibernation. These data suggest a two-s...

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The molecular basis of aminoacylase 1 deficiency

Cited by 30 publications

References 21 publications

Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

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

Metabolic cycles in a circannual hibernator

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