AMPD3
AMP-deaminata 3 je enzim koji je kod ljudi kodiran genom AMPD3.[5][6]
Ovaj gen kodira člana porodice gena AMP-deaminaza. Kodirani protein je visoko regulirani enzim koji katalizira hidrolitsku deaminaciju adenozin-monofosfata u inozin-monofosfat, tačku grananja u adenilatnom katabolitskom putu. Ovaj gen kodira izoforme eritrocita (E), dok drugi članovi porodice kodiraju izoforme koje prevladavaju u mišićnim (M) i jetrenim (L) ćelijama. Mutacije u ovom genu dovode do klinički asimptomskog, autosomno recesivnog stanja, nedostatka AMP-deaminaze eritrocita. Opisane su i alternativno prerađenesu varijante transkripta koje kodiraju različite izoforme ovog gena.[6]
Aminokiselinska sekvenca
Dužina polipeptidnog lanca je 767 aminokiselina, a molekulska težina 88.812 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MPRQFPKLNI | SEVDEQVRLL | AEKVFAKVLR | EEDSKDALSL | FTVPEDCPIG | ||||
| QKEAKERELQ | KELAEQKSVE | TAKRKKSFKM | IRSQSLSLQM | PPQQDWKGPP | ||||
| AASPAMSPTT | PVVTGATSLP | TPAPYAMPEF | QRVTISGDYC | AGITLEDYEQ | ||||
| AAKSLAKALM | IREKYARLAY | HRFPRITSQY | LGHPRADTAP | PEEGLPDFHP | ||||
| PPLPQEDPYC | LDDAPPNLDY | LVHMQGGILF | VYDNKKMLEH | QEPHSLPYPD | ||||
| LETYTVDMSH | ILALITDGPT | KTYCHRRLNF | LESKFSLHEM | LNEMSEFKEL | ||||
| KSNPHRDFYN | VRKVDTHIHA | AACMNQKHLL | RFIKHTYQTE | PDRTVAEKRG | ||||
| RKITLRQVFD | GLHMDPYDLT | VDSLDVHAGR | QTFHRFDKFN | SKYNPVGASE | ||||
| LRDLYLKTEN | YLGGEYFARM | VKEVARELEE | SKYQYSEPRL | SIYGRSPEEW | ||||
| PNLAYWFIQH | KVYSPNMRWI | IQVPRIYDIF | RSKKLLPNFG | KMLENIFLPL | ||||
| FKATINPQDH | RELHLFLKYV | TGFDSVDDES | KHSDHMFSDK | SPNPDVWTSE | ||||
| QNPPYSYYLY | YMYANIMVLN | NLRRERGLST | FLFRPHCGEA | GSITHLVSAF | ||||
| LTADNISHGL | LLKKSPVLQY | LYYLAQIPIA | MSPLSNNSLF | LEYSKNPLRE | ||||
| FLHKGLHVSL | STDDPMQFHY | TKEALMEEYA | IAAQVWKLST | CDLCEIARNS | ||||
| VLQSGLSHQE | KQKFLGQNYY | KEGPEGNDIR | KTNVAQIRMA | FRYETLCNEL | ||||
| SFLSDAMKSE | EITALTN |
Modelni organizmi
| Svojstvo | Fenotip |
|---|---|
| Vijabilnost homozigota | Normalan |
| Studija recesivne letalnosti | Normalan |
| Plodnost | Normalan |
| Tjelesna težina | Normalan |
| Test otvorenog polja: anksioznost | Normalan |
| Neurološka procjena | Normalan |
| Snaga stiska | Normalan |
| Test vruće ploče | Normalan |
| Dismorfologija | Normalan |
| Indirektna kalorimetrija | Normalan |
| Test tolerancije glukoze | Normalan |
| Slušni odgovor moždanog stabla | Normalan |
| DEXA | Normalan |
| Radiografija | Normalan |
| Tjelesna temperatura | Normalan |
| Morfologija oka | Normalan |
| Klinička hemija (nalaz) | Normalan |
| Plazmatski imunoglobulini | Nenormalan |
| Hematologija | Normalan |
| Leukociti periferne krvi | Nenormalan |
| Mikronukleus test | Normalan |
| Težina srca | Normalan |
| Histopatologija mozga | Nenormalan |
| Histopatologija oka | Normalan |
| MikroCT i kvantitativni faksitron | Nenormalan |
| Salmonella infekcija | Normal[8] |
| Citrobacter infekcija | Normal[9] |
| Svi testovi i analize su iz [10][11] |
U proučavanju PNPO funkcije, korišteni su modelni organizmi. Uvjetna linija nokaut-miševa, zvana Pnpotm1a (KOMP) Wtsi,[12][13] generirana je kao dio programa Međunarosnog konzorcija za nokaut-miševe – visokopropusnog projekta mutageneze za generiranje i distribuciju životinjskih modela bolesti zainteresiranim naučnicima.[14][15][16]
Muške i ženske životinje prolazile su standardizirani fenotipski skrining, kako bi se utvrdili efekti delecije.[10][17] Od 24 izvedena testa ina mutantnim miševima, uočene su dvije značajne abnormalnosti.[10] Tokom gestacije, nije utvrđen homozigotni mutantni embrion, pa tako nijedan nije preživio do odvikavanja. Preostali testovi su izvedeni na mutiranim heterozigotnim odraslim miševima; opažene su četiri značajijne abnormalnosti kod ovih životinja.[10] Druga mišja linija, zvana Ampd3T689A, generirana je mutagenezom ENU.[18] Ovaj miš nosi mutaciju koja povećava funkciju AMPD3. Mutantne životinje imaju značajno kraći životni vijek crvenih krvnih ćelija, cikličku eritropoezu, splenomegaliju i otpornost na infekciju sa Plasmodium chabaudi .
Reference
- ^ a b c GRCh38: Ensembl release 89: ENSG00000133805 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005686 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mahnke-Zizelman DK, Sabina RL (oktobar 1992). "Cloning of human AMP deaminase isoform E cDNAs. Evidence for a third AMPD gene exhibiting alternatively spliced 5'-exons". The Journal of Biological Chemistry. 267 (29): 20866–77. doi:10.1016/S0021-9258(19)36768-7. PMID 1400401.
- ^ a b "Entrez Gene: AMPD3 adenosine monophosphate deaminase (isoform E)".
- ^ "UniProt, Q01432". Pristupljeno 15. 8. 2021.
- ^ "Salmonella infection data for Pnpo". Wellcome Trust Sanger Institute.
- ^ "Citrobacter infection data for Pnpo". Wellcome Trust Sanger Institute.
- ^ a b c d Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
- ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ^ "International Knockout Mouse Consortium". Arhivirano s originala, 3. 4. 2012. Pristupljeno 15. 8. 2021.
- ^ "Mouse Genome Informatics".
- ^ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- ^ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ^ Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
- ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
- ^ Hortle E, Nijagal B, Bauer DC, Jensen LM, Ahn SB, Cockburn IA, Lampkin S, Tull D, McConville MJ, McMorran BJ, Foote SJ, Burgio G (septembar 2016). "Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice". Blood. 128 (9): 1290–301. doi:10.1182/blood-2015-09-666834. PMC 5009516. PMID 27465915.
Dopunska literatura
- Zydowo MM (1994). "Regulatory effects of the lipid-cytosolic enzyme interaction: AMP deaminase". Acta Biochimica Polonica. 40 (4): 429–32. doi:10.18388/abp.1993_4780. PMID 8140814.
- Yamada Y, Goto H, Ogasawara N (novembar 1992). "Cloning and nucleotide sequence of the cDNA encoding human erythrocyte-specific AMP deaminase". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1171 (1): 125–8. doi:10.1016/0167-4781(92)90153-Q. PMID 1420359.
- Ogasawara N, Goto H, Yamada Y, Nishigaki I, Itoh T, Hasegawa I, Park KS (januar 1987). "Deficiency of AMP deaminase in erythrocytes". Human Genetics. 75 (1): 15–8. doi:10.1007/BF00273831 (neaktivno 31. 5. 2021). PMID 3804327.CS1 održavanje: DOI nije aktivan od 2021 (link)
- Yamada Y, Goto H, Murase T, Ogasawara N (decembar 1994). "Molecular basis for human erythrocyte AMP deaminase deficiency: screening for the major point mutation and identification of other mutations". Human Molecular Genetics. 3 (12): 2243–5. doi:10.1093/hmg/3.12.2243. PMID 7881427.
- Yamada Y, Goto H, Ogasawara N (februar 1994). "A point mutation responsible for human erythrocyte AMP deaminase deficiency". Human Molecular Genetics. 3 (2): 331–4. doi:10.1093/hmg/3.2.331. PMID 8004104.
- Mahnke-Zizelman DK, Eddy R, Shows TB, Sabina RL (april 1996). "Characterization of the human AMPD3 gene reveals that 5' exon usage is subject to transcriptional control by three tandem promoters and alternative splicing". Biochimica et Biophysica Acta. 1306 (1): 75–92. doi:10.1016/0167-4781(95)00231-6. PMID 8611627.
- Fortuin FD, Morisaki T, Holmes EW (juli 1996). "Subunit composition of AMPD varies in response to changes in AMPD1 and AMPD3 gene expression in skeletal muscle". Proceedings of the Association of American Physicians. 108 (4): 329–33. PMID 8863347.
- Mahnke-Zizelman DK, D'cunha J, Wojnar JM, Brogley MA, Sabina RL (septembar 1997). "Regulation of rat AMP deaminase 3 (isoform C) by development and skeletal muscle fibre type". The Biochemical Journal. 326 ( Pt 2) (2): 521–9. doi:10.1042/bj3260521. PMC 1218700. PMID 9291127.
- Yamada Y, Goto H, Wakamatsu N, Ogasawara N (2001). "A rare case of complete human erythrocyte AMP deaminase deficiency due to two novel missense mutations in AMPD3". Human Mutation. 17 (1): 78. doi:10.1002/1098-1004(2001)17:1<78::AID-HUMU21>3.0.CO;2-B. PMID 11139257.
- Mahnke-Zizelman DK, Sabina RL (novembar 2002). "N-terminal sequence and distal histidine residues are responsible for pH-regulated cytoplasmic membrane binding of human AMP deaminase isoform E". The Journal of Biological Chemistry. 277 (45): 42654–62. doi:10.1074/jbc.M203473200. PMID 12213808. S2CID 25657474.
- Tomikura Y, Hisatome I, Tsuboi M, Yamawaki M, Shimoyama M, Yamamoto Y, Sasaki N, Ogino K, Igawa O, Shigemasa C, Ishiguro S, Ohgi S, Nanba E, Shiota G, Morisaki H, Morisaki T, Kitakaze M (mart 2003). "Coordinate induction of AMP deaminase in human atrium with mitochondrial DNA deletion" (PDF). Biochemical and Biophysical Research Communications. 302 (2): 372–6. doi:10.1016/S0006-291X(03)00160-8. PMID 12604357. Arhivirano s originala (PDF), 13. 3. 2022. Pristupljeno 15. 8. 2021.
- Mahnke DK, Sabina RL (april 2005). "Calcium activates erythrocyte AMP deaminase [isoform E (AMPD3)] through a protein-protein interaction between calmodulin and the N-terminal domain of the AMPD3 polypeptide". Biochemistry. 44 (14): 5551–9. doi:10.1021/bi048121p. PMID 15807549.
- Sabina RL, Waldenström A, Ronquist G (maj 2006). "The contribution of Ca+ calmodulin activation of human erythrocyte AMP deaminase (isoform E) to the erythrocyte metabolic dysregulation of familial phosphofructokinase deficiency". Haematologica. 91 (5): 652–5. PMID 16670071.
Vanjski linkovi
- Lokacija ljudskog genoma AMPD3 i stranica sa detaljima o genu AMPD3 u UCSC Genome Browseru.
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