HMBS
Porfobilinogen-deaminaza (hidroksimetilbilan-sintaza ili uroporfirinogen I-sintaza) je enzim (EC 2.5.1.61) koji je kod ljudi kodiran genom HMBS. Porfobilinogen-deaminaza uključena je u treći korak biosintetskog puta hema. Katalizira kondenzaciju četiri molekule porfobilinogena od glave do repa u linearni hidroksimetilbilan dok oslobađa četiri molekule amonijaka:
- 4 porfobilinogen + H2O hidroksimetilbilan+ 4 NH3
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 361 aminokiselina, a molekulska težina 39.330 Da.[5]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MSGNGNAAAT | AEENSPKMRV | IRVGTRKSQL | ARIQTDSVVA | TLKASYPGLQ | ||||
| FEIIAMSTTG | DKILDTALSK | IGEKSLFTKE | LEHALEKNEV | DLVVHSLKDL | ||||
| PTVLPPGFTI | GAICKRENPH | DAVVFHPKFV | GKTLETLPEK | SVVGTSSLRR | ||||
| AAQLQRKFPH | LEFRSIRGNL | NTRLRKLDEQ | QEFSAIILAT | AGLQRMGWHN | ||||
| RVGQILHPEE | CMYAVGQGAL | GVEVRAKDQD | ILDLVGVLHD | PETLLRCIAE | ||||
| RAFLRHLEGG | CSVPVAVHTA | MKDGQLYLTG | GVWSLDGSDS | IQETMQATIH | ||||
| VPAQHEDGPE | DDPQLVGITA | RNIPRGPQLA | AQNLGISLAN | LLLSKGAKNI | ||||
| LDVARQLNDA | H |
Struktura i funkcija
urediFunkcionalno, porfobilinogen-deaminaza katalizira gubitak amonijaka iz monofom-porfobilinogena (deaminacija) i njegovu kasniju polimerizaciju u linearni tetrapirol, koji se oslobađa kao hidroksimetilbilan:
Struktura porfobilinogen-deaminaze od 40-42 kDa, koja je visoko konzervirana među organizmima, sastoji se od tri domena.[6][7] Domeni 1 i 2 su strukturno vrlo slični: kod ljudi, svaki se sastoji od po pet beta-listova i tri alfa-heliksa.[8] Domen 3 je pozicioniran između druga dva i ima spljoštenu geometriju beta-lista. Dipirol, kofaktor ovog enzima koji se sastoji od dvije kondenzirane molekule porfobilinogena, kovalentno je vezan za domen 3 i proteže se u aktivno mjesto, rascjep između domena 1 i 2.[9] Pokazalo se da nekoliko pozitivno nabijenih ostataka arginina, pozicioniranih prema aktivnom mjestu iz domena 1 i 2, stabiliziraju karboksilatne funkcije na dolaznom porfobilinogenu, kao i rastući lanac pirola. Ove strukturne karakteristike vjerovatno pogoduju stvaranju konačnog proizvoda hidroksimetilbilana.[10] Porfobilinogen-deaminaza obično postoji u dimernim jedinicama u ćelijskoj citoplazmi.
Reakcijski mehanizam
urediVjeruje se da prvi korak uključuje eliminaciju E1 amonijaka iz porfobilinogena, stvarajući međuprodukt karbokacije (1).[11] Ovaj intermedijer zatim napada dipirolski kofaktor porfobilinogen-deaminaze, koji nakon gubitka protona daje trimer kovalentno vezan za enzim (2). Ovaj međuprodukt je tada otvoren za daljnju reakciju s porfobilinogenom (1 i 2 ponovljena još tri puta). Kada se formira heksamer, hidroliza omogućava oslobađanje hidroksimetilbilana, kao i regeneraciju kofaktora (3).[12][13]
Patologija
urediNajpoznatiji zdravstveni problem koji uključuje porfobilinogen-deaminazu je akutna intermitentna porfirija, autosomno dominantni genetički poremećaj, u kojem se nedovoljno stvara hidroksimetilbilan, što dovodi do nakupljanja porfobilinogena u citoplazmi. To je uzrokovano mutacijom gena koja u 90% slučajeva uzrokuje smanjene količine enzima. Međutim, opisane su mutacije u kojima su manje aktivni enzimi i/ili različite izoforme.[14][15][16]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000256269 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032126 - Ensembl, maj 2017
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- ^ Battersby AR (decembar 2000). "Tetrapyrroles: the pigments of life". Nat Prod Rep. 17 (6): 507–26. doi:10.1039/b002635m. PMID 11152419.
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Dopunska literatura
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- Gu XF, de Rooij F, Voortman G, et al. (1992). "High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria". Am. J. Hum. Genet. 51 (3): 660–5. PMC 1682727. PMID 1496994.
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Vanjski linkovi
uredi