Disease relevance of ASAH1

• Interestingly, 10 of 15 primary prostate cancers examined by Western blotting overexpressed acid ceramidase (AC), suggesting that ceramide deacylation might serve to negate elevated levels of ceramide, creating a more antiapoptotic phenotype [1].
• Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles [2].
• Eight of the 14 patients had relapsed or had refractory non-Hodgkin's lymphoma (NHL) and received rhGM-CSF after intensive chemotherapy with novantrone (NO) and high-dose Ara-C (AC) (NOAC) as salvage regimen [3].
• Hypoxia increased AC RNA expression; the AC inhibitor NOE enhanced 4-HPR-induced ceramide species increase and cytotoxicity [4].
• The PHP domain is highly conserved in all bacterial polymerase III alpha subunits, but in proteobacteria and mycoplasmas, the conserved motifs are distorted, suggesting a loss of the enzymatic activity [5].

Psychiatry related information on ASAH1

• Significantly higher olfaction thresholds were observed in UV line and AC line workers and finishers of UV/AC surface-coated wood products [6].
• I believe these data are essential to those in decision making positions and ASAHP would be an appropriate organization to collect and disseminate these data [7].
• Aberrant AC activity also has been described in Alzheimer's disease, and overexpression of AC may prevent insulin resistant (Type II) diabetes induced by free fatty acids [8].

High impact information on ASAH1

• In patients presumed to have the most severe GnRH deficiency (PHP), responses of both FSH and luteinizing hormone (LH) were small and delayed, and no increase in plasma estradiol occurred during the 5 d of GnRH injections [9].
• Here, we show that the abundant DEAD-box RNA helicase p72, but not its close relative p68, affects the splicing of alternative exons containing AC-rich exon enhancer elements [10].
• Interestingly, knockdown of endogenous AC by RNA interference attenuated cyclooxygenase 2 induction by TNFalpha and subsequent PGE(2) biosynthesis [11].
• Frequency of Tax-specific CD8(+) T cells in AC was related to proviral load in HLA-A*0201 [12].
• In addition, the AC tyrosines regulate tyrosine phosphorylation of Vav1 [13].

Chemical compound and disease context of ASAH1

• We measured cAMP production in response to agonists in cultured skin fibroblasts from subjects with pseudohypoparathyroidism type Ib (PHP Ib; normal phenotype, resistance to PTH only, normal guanine nucleotide stimulatory coupling protein activity) and skin fibroblasts from normal subjects [14].
• By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls [15].
• Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara-C (AC) (NOAC) was active in refractory non-Hodgkin's lymphoma (NHL) but myelosuppression was dose-limiting [16].
• This case shows that it is possible for a response mimicking that of PHP type II to occur when the serum calcidiol level is low due to causes other than hypocalcemia and secondary hyperparathyroidism [17].
• In the present study, serum total (TC), free (FC), and acyl (AC) carnitine levels were investigated in 20 healthy controls (13 males and 7 females) and 27 patients (10 males and 17 females) with chronic pyelonephritis (CPN) undergoing regular chronic hemodialysis (CHD) [18].

Biological context of ASAH1

• Acid ceramidase (N-acylsphingosine deacylase, EC 3.5.1.23) is the lysosomal enzyme catalyzing the hydrolysis of ceramide to sphingosine and free fatty acid [19].
• A homoallelic point mutation (T222K) was also identified in the AC gene of a patient suffering from Farber disease, further confirming the authenticity of the full-length cDNA [20].
• This was confirmed in AC-overexpressing cells in which we observed decreased sensitivity to apoptosis following treatment with Apoptin [1].
• Finally, three new missense mutations, E138V, R254G, and P362R, were identified in the human AC gene from FD patients [21].
• These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect [22].

Anatomical context of ASAH1

• Secretion of hAC by either fibroblasts or acid ceramidase cDNA-transfected COS cells is extraordinarily low [23].
• Transient expression of the full-length cDNA in COS-1 cells led to a 10-fold increase in AC activity [20].
• The biosynthesis of human acid ceramidase (hAC) starts with the expression of a single precursor polypeptide of approximately 53-55 kDa, which is subsequently processed to the mature, heterodimeric enzyme (40 + 13 kDa) in the endosomes/lysosomes [23].
• Two minor AC transcripts of 1.7 and 1.2 kb also were detected in heart and skeletal muscle [21].
• Metabolic labeling studies in fibroblasts of four patients showed that even though acid ceramidase precursor protein was synthesized in these individuals, rapid proteolysis of the mutated, mature acid ceramidase occurred within the lysosome [24].

Associations of ASAH1 with chemical compounds

• Human acid ceramidase ((AC) N-acylsphingosine amidohydrolase, EC 3.5. 1.23) hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid [20].
• 2-Anthracenecarboxylic acid (AC) makes a very stable 1:2 inclusion complex with gamma-cyclodextrin (gamma-CDx) (K(1) = 161 +/- 25 M(-1), K(2) = 38 500 +/- 3300 M(-1) at 25 degrees C) [25].
• In these cases, the pyrophosphate may be hydrolyzed by a stand-alone phosphatase, and candidates for such a role were identified among bacterial PHP superfamily members [5].
• The predicted catalytic site of the PHP superfamily consists of four motifs containing conserved histidine residues that are likely to be involved in metal-dependent catalysis of phosphoester bond hydrolysis [5].
• The alpha subunits of bacterial DNA polymerase III and two distinct family X DNA polymerases are shown to contain an N-terminal domain that defines a novel enzymatic superfamily, designated PHP, after polymerase and histidinol phosphatase [5].

Analytical, diagnostic and therapeutic context of ASAH1

• The human AC gene was mapped to the chromosomal region 8p21.3-p22 by in situ hybridization and FISH analyses, syntenic with the mouse chromosomal location [21].
• One PHP 1b kindred (family M) was informative for a intragenic polymorphism in exon 3 of the PTH gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis [26].
• The main outcome measures were CAC and AC, measured by electron beam tomography [27].
• Interestingly, total testosterone was an independent risk factor for AC in all subjects after controlling for PCOS, age, and body mass index (P = 0.034) [27].
• The expression of AC in normal thyroids and thyroid tumors was examined by semi-quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR) [28].

References