Disease relevance of AMPD1

• We conclude that the Q12X mutation in AMPD1 may result in a mild clinical effect; that it is frequent in the Spanish population, and therefore frequently associated with other metabolic diseases; and that the effect of the association of AMPD and PPL deficiencies seems to be neutral [1].
• This enzyme activity is presumed to be important in skeletal muscle because a metabolic myopathy develops in individuals with an inherited deficiency of AMPD1 [2].
• A common variant of the AMPD1 gene predicts improved survival in patients with ischemic left ventricular dysfunction [3].
• Consequently, genetic tests for abnormal AMPD1 expression designed to diagnose patients with metabolic myopathy, and to evaluate genetic markers for clinical outcome in heart disease should not be based solely on the detection of a single mutant allele [4].
• Myoadenylate deaminase deficiency with progressive muscle weakness and atrophy caused by new missense mutations in AMPD1 gene: case report in a Japanese patient [5].

Psychiatry related information on AMPD1

• Compared to control brain, Alzheimer's disease brain AMP deaminase activity is 1.6- to 2.4-fold greater in the regions examined--the cerebellum, occipital cortex, and temporal cortex [6].

High impact information on AMPD1

• Alternative splicing eliminates exon 2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle [7].
• More than 100 patients with AMPD1 deficiency have been reported to have symptoms of a metabolic myopathy, but it is apparent many individuals with this inherited defect are asymptomatic given the prevalence of this mutant [7].
• Transfection studies with human minigene constructs demonstrate that alternative splicing of the primary transcript of human AMPD1 is controlled by tissue-specific and stage-specific signals [7].
• When the incubation medium was alkalinized in the presence of glucose, the 15-fold increase in the conversion of AMP to hypoxanthine proceeded exclusively by way of AMP deaminase but a small recycling of adenosine could also be evidenced [8].
• Myoadenylate deaminase deficiency. Functional and metabolic abnormalities associated with disruption of the purine nucleotide cycle [9].

Chemical compound and disease context of AMPD1

• The increased conversion of adenosine monophosphate to adenosine, which in turn attenuates the expression of tumor necrosis factor-alpha (TNF-alpha) expression, has been suggested as a putative mechanism for prolonged survival in patients with congestive heart failure (CHF) carrying the mutant AMPD1 allele [10].
• Myoadenylate deaminase deficiency, a purine nucleotide cycle defect, is somewhat controversial and is characterized by exercise-related cramps leading rarely to myoglobinuria [11].
• Calculations based on the kinetic data obtained in this study show that the AMP deaminase reaction can account for the well-established alteration of adenine nucleotide metabolism that is observed following addition of glucose or 2-deoxyglucose to intact ascites cells [12].
• After ischemic exercise tests, performed to detect glycogenoses or myoadenylate deaminase (EC 3.5.4.6) deficiency, the increases in serum lactate and ammonia usually are measured [13].
• Ischaemic exercise test in myoadenylate deaminase deficiency and McArdle's disease: measurement of plasma adenosine, inosine and hypoxanthine [14].

Biological context of AMPD1

• Multifactorial correlative analyses demonstrate that AMPD1 genotype has the greatest effect on enzyme activity [15].
• Homozygotes for the AMPD1 normal allele have high enzyme activities, and heterozygotes display intermediate activities [15].
• An AMPD1 mutant allele frequency of 13.7 and a 1.7% incidence of enzyme deficiency was found across 175 healthy subjects [15].
• AMP deaminase (AMPD) is characterized by a multigene family in rodents and man [16].
• The entire sets of active enzymes are used to extend our understanding of the contractile protein binding of AMPD [17].

Anatomical context of AMPD1

• In humans, four AMP deaminase variants, termed M (muscle), L (liver), E1, and E2 (erythrocyte) can be distinguished by a variety of biochemical and immunological criteria [18].
• The reversible association of AMP deaminase (AMPD, EC 3.5.4.6) with elements of the contractile apparatus is an identified mechanism of enzyme regulation in mammalian skeletal muscle [17].
• Interaction between these functionally distinct elements may be required for regulating the expression of AMPD1 during myocyte differentiation and in different muscle fiber types [2].
• The second element (-60 to -40) has properties of a stage-specific promoter in that it is essential for muscle-specific expression of the AMPD1 promoter, does not confer muscle-specific expression on a heterologous promoter construct, and interacts with a protein(s) restricted to nuclei of differentiated myotubes [2].
• Prior studies have demonstrated that AMPD1 binds to myosin heavy chain (MHC) in vitro; binding to the myofibril varies with the state of muscle contraction in vivo, and binding of AMPD1 to MHC is required for activation of this enzyme in myocytes [19].

Associations of AMPD1 with chemical compounds

• Finally, AMPD1 and a series of N-truncated AMPD3 enzymes are used to show that these behaviors are specific to isoform E and require up to 48 N-terminal amino acids, even though this stretch of sequence contains no histidine residues [20].
• CASE REPORT: In a 53-year-old man with easy fatigability and myalgia since boyhood, primary MADD was diagnosed based upon slightly, but recurrently elevated creatine-kinase, absent staining for MAD on muscle biopsy, markedly reduced MAD activity in the muscle homogenate, and the C34T mutation within exon 2 of the AMPD1 gene [21].
• AMP deaminase (AMPD) converts AMP to IMP and is a diverse and highly regulated enzyme that is a key component of the adenylate catabolic pathway [22].
• In addition, in vivo modulation of phosphoinositide levels leads to a change in the soluble and membrane-associated pools of AMPD activity [22].
• We demonstrate that endogenous rat brain AMPD and the human AMPD3 recombinant enzymes specifically bind inositide-based affinity probes and to mixed lipid micelles that contain phosphatidylinositol 4,5-bisphosphate [22].

Physical interactions of AMPD1

• AMP deaminase displaces membrane bound glyceraldehyde 3-phosphate dehydrogenase in roughly a dose-response manner [23].
• Filamentous aggregates of native titin and binding of C-protein and AMP-deaminase [24].

Regulatory relationships of AMPD1

• When placed in a prokaryotic expression vector, the human AMPD2 cDNA expresses AMP deaminase activity which can be precipitated with polyclonal antisera specific for isoform L [25].
• METHODS AND RESULTS: AMPD1 genotype was determined in 132 patients with advanced CHF and 91 control reference subjects by use of a polymerase chain reaction-based, allele-specific oligonucleotide detection assay [26].
• We hypothesize that during periods of high energy demand, exclusively AMP deaminase is activated as a means (1) to push the myokinase reaction toward ATP synthesis, (2) to supply allosteric effectors, and (3) to remove some of the accumulating protons through the formation of ammonium, all at the expense of the adenylate pool [27].

Other interactions of AMPD1

• This study identifies a third human AMP deaminase gene, AMPD3 [18].
• In contrast, the predicted N-terminal domains of the human AMPD1 and AMPD2 polypeptides are unique [25].
• In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression [28].
• In conclusion, mtDNA deletion coordinately induces AMP deaminase to contribute to the loss of atrial adenine nucleotides through degrading AMP excessively [29].
• This region of AMPD1 shares sequence similarity with several regions of titin, another MHC binding protein [19].

Analytical, diagnostic and therapeutic context of AMPD1

• Gel filtration analysis demonstrates native tetrameric structures for all recombinant proteins, except the wild type AMPD1 enzyme, which forms aggregates of tetramers that disperse upon cleavage of N-terminal residues at 4 degreesC [30].
• CONCLUSIONS: After the onset of CHF symptoms, the mutant AMPD1 allele is associated with prolonged probability of survival without cardiac transplantation [26].
• The OR of surviving without cardiac transplantation >/=5 years after initial hospitalization for CHF symptoms was 8.6 times greater (95% CI: 3.05, 23.87) in those patients carrying >/=1 mutant AMPD1 allele than in those carrying 2 wild-type AMPD1 +/+ alleles [26].
• In addition, blood adenosine concentration was measured by liquid chromatography/mass spectrometry (LC/MS) in 21 healthy subjects with established AMPD1 genotype at rest and following exhaustive exercise [31].
• Allele-specific PCR amplification assays demonstrated that the common Q12X (C34T) and P48L (C143T) mutations were not found within their AMPD1 genes [32].

References