Izvorni kôd stranice HMBS

{{Infokutija gen}}
'''Porfobilinogen-deaminaza''' ('''hidroksimetilbilan-sintaza''' ili  '''uroporfirinogen I-sintaza''') je [[enzim]] ([[EC broj|EC 2.5.1.61]]) koji je kod [[ljudi]] [[kodon|kodiran]] [[gen]]om '''HMBS'''. Porfobilinogen-deaminaza uključena je u treći korak biosintetskog puta [[hem]]a. Katalizira kondenzaciju četiri molekule [[porfobilinogen]]a od glave do repa u linearni [[hidroksimetilbilan]] dok oslobađa četiri molekule [[amonijak]]a:
: 4 [[porfobilinogen]] + H<sub>2</sub>O<math>\rightleftharpoons</math> [[hidroksimetilbilan]]+ 4 NH<sub>3</sub>

==Aminokiselinska sekvenca==
Dužina [[peptid|polipeptidnog]] lanca je 361  [[aminokiselina]], a [[molekularna masa|molekulska težina]] 39.330 [[dalton (jedinica)|Da]].<ref name="UniProt">{{cite web|url=http://www.uniprot.org/uniprot/P08397#sequences |title=UniProt, P08397 |access-date=23. 8. 2021}}</ref>

<table  style="font-family:monospace;">
<tr style="text-align:right;"><th>10</th><th></th><th>20</th><th></th><th>30</th><th></th><th>40</th><th></th><th>50</th></tr>
<tr style="background-color: #eee;"><td>MSGNGNAAAT</td><td style="background-color: #f9f9f9;"></td><td>AEENSPKMRV</td><td style="background-color: #f9f9f9;"></td><td>IRVGTRKSQL</td><td style="background-color: #f9f9f9;"></td><td>ARIQTDSVVA</td><td style="background-color: #f9f9f9;"></td><td>TLKASYPGLQ</td></tr>
<tr style="background-color: #eee;"><td>FEIIAMSTTG</td><td style="background-color: #f9f9f9;"></td><td>DKILDTALSK</td><td style="background-color: #f9f9f9;"></td><td>IGEKSLFTKE</td><td style="background-color: #f9f9f9;"></td><td>LEHALEKNEV</td><td style="background-color: #f9f9f9;"></td><td>DLVVHSLKDL</td></tr>
<tr style="background-color: #eee;"><td>PTVLPPGFTI</td><td style="background-color: #f9f9f9;"></td><td>GAICKRENPH</td><td style="background-color: #f9f9f9;"></td><td>DAVVFHPKFV</td><td style="background-color: #f9f9f9;"></td><td>GKTLETLPEK</td><td style="background-color: #f9f9f9;"></td><td>SVVGTSSLRR</td></tr>
<tr style="background-color: #eee;"><td>AAQLQRKFPH</td><td style="background-color: #f9f9f9;"></td><td>LEFRSIRGNL</td><td style="background-color: #f9f9f9;"></td><td>NTRLRKLDEQ</td><td style="background-color: #f9f9f9;"></td><td>QEFSAIILAT</td><td style="background-color: #f9f9f9;"></td><td>AGLQRMGWHN</td></tr>
<tr style="background-color: #eee;"><td>RVGQILHPEE</td><td style="background-color: #f9f9f9;"></td><td>CMYAVGQGAL</td><td style="background-color: #f9f9f9;"></td><td>GVEVRAKDQD</td><td style="background-color: #f9f9f9;"></td><td>ILDLVGVLHD</td><td style="background-color: #f9f9f9;"></td><td>PETLLRCIAE</td></tr>
<tr style="background-color: #eee;"><td>RAFLRHLEGG</td><td style="background-color: #f9f9f9;"></td><td>CSVPVAVHTA</td><td style="background-color: #f9f9f9;"></td><td>MKDGQLYLTG</td><td style="background-color: #f9f9f9;"></td><td>GVWSLDGSDS</td><td style="background-color: #f9f9f9;"></td><td>IQETMQATIH</td></tr>
<tr style="background-color: #eee;"><td>VPAQHEDGPE</td><td style="background-color: #f9f9f9;"></td><td>DDPQLVGITA</td><td style="background-color: #f9f9f9;"></td><td>RNIPRGPQLA</td><td style="background-color: #f9f9f9;"></td><td>AQNLGISLAN</td><td style="background-color: #f9f9f9;"></td><td>LLLSKGAKNI</td></tr>
<tr style="background-color: #eee;"><td>LDVARQLNDA</td><td style="background-color: #f9f9f9;"></td><td>H</td></tr>
</table>
{{legenda aminokiselina}}

== Struktura i funkcija ==
Funkcionalno, porfobilinogen-deaminaza katalizira gubitak amonijaka iz monofom-porfobilinogena ([[deaminacija]]) i njegovu kasniju polimerizaciju u linearni tetrapirol, koji se oslobađa kao hidroksimetilbilan:
[[Slika:Overall PBG Deaminase Reaction.png|center|550px|Sveukupna reakcija PB-deaminaze]]

Struktura porfobilinogen-deaminaze od 40-42 kDa, koja je visoko konzervirana među organizmima, sastoji se od tri domena.<ref name="pmid2609111">{{cite journal |vauthors=Lannfelt L, Wetterberg L, Lilius L, Thunell S, Jörnvall H, Pavlu B, Wielburski A, Gellerfors P | title = Porphobilinogen deaminase in human erythrocytes: purification of two forms with apparent molecular weights of 40 kDa and 42 kDa | journal = Scand. J. Clin. Lab. Invest. | volume = 49 | issue = 7 | pages = 677–84 |date=novembar 1989  | pmid = 2609111 | doi = 10.3109/00365518909091544}}</ref><ref name="pmid1522882">{{cite journal |vauthors=Louie GV, Brownlie PD, Lambert R, Cooper JB, Blundell TL, Wood SP, Warren MJ, Woodcock SC, Jordan PM | s2cid = 4264432 | title = Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site | journal = Nature | volume = 359 | issue = 6390 | pages = 33–9 |date=septembar 1992  | pmid = 1522882 | doi = 10.1038/359033a0 | bibcode = 1992Natur.359...33L }}</ref>  Domeni 1 i 2 su strukturno vrlo slični: kod ljudi, svaki se sastoji od po pet [[beta-list]]ova i tri [[alfa-heliks]]a.<ref name="pmid19207107">{{cite journal |vauthors=Gill R, Kolstoe SE, Mohammed F, Al D-Bass A, Mosely JE, Sarwar M, Cooper JB, Wood SP, Shoolingin-Jordan PM | title = Structure of human porphobilinogen deaminase at 2.8 Å: the molecular basis of acute intermittent porphyria | journal = Biochem. J. | volume = 420 | issue = 1 | pages = 17–25 |date=maj 2009  | pmid = 19207107 | doi = 10.1042/BJ20082077 | url = https://hal.archives-ouvertes.fr/hal-00479112/file/PEER_stage2_10.1042%252FBJ20082077.pdf }}</ref> Domen 3 je pozicioniran između druga dva i ima spljoštenu geometriju beta-lista. Dipirol, [[kofaktor (biohemija)|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.<ref name="pmid3079571">{{cite journal |vauthors=Jordan PM, Warren MJ | title = Evidence for a dipyrromethane cofactor at the catalytic site of E. coli porphobilinogen deaminase | journal = FEBS Lett. | volume = 225 | issue = 1–2 | pages = 87–92 |date=decembar 1987  | pmid = 3079571 | doi = 10.1016/0014-5793(87)81136-5| s2cid = 13483654 }}</ref>  Pokazalo se da nekoliko pozitivno nabijenih ostataka [[arginin]]a, pozicioniranih prema aktivnom mjestu iz domena 1 i 2, stabiliziraju karboksilatne funkcije na dolaznom porfobilinogenu, kao i rastući lanac [[pirol]]a. Ove strukturne karakteristike vjerovatno pogoduju stvaranju konačnog proizvoda hidroksimetilbilana.<ref name="pmid2025226">{{cite journal |vauthors=Lander M, Pitt AR, Alefounder PR, Bardy D, Abell C, Battersby AR | title = Studies on the mechanism of hydroxymethylbilane synthase concerning the role of arginine residues in substrate binding | journal = Biochem. J. | volume = 275 | issue = 2| pages = 447–52 |date=april 1991  | pmid = 2025226 | pmc = 1150073 | doi = 10.1042/bj2750447}}</ref>  Porfobilinogen-deaminaza obično postoji u dimernim jedinicama u ćelijskoj [[citoplazma|citoplazmi]].

== Reakcijski mehanizam ==
[[Slika:Full PBG Deaminase Mechanism.png|center|550px|Puni mehanizam PBG-deaminaze]]
[[slika:Heme synthesis.png|center|framed|Sinteza hema&mdash;reakcija se javlja u [[citoplazma|citoplazmi]] i nekim  [[mitohondrija]]ma (žuto)]]
Vjeruje se da prvi korak uključuje [[eliminacija E1|eliminaciju E1]] [[amonijak]]a iz porfobilinogena, stvarajući međuprodukt karbokacije (1).<ref name=Pichon_1992>{{cite journal |vauthors=Pichon C, Clemens KR, Jacobson AR, Ian Scott A | title = On the mechanism of porphobilinogen deaminase. Design, synthesis, and enzymatic reactions of novel porphobilinogen analogs. |url=https://archive.org/details/sim_tetrahedron_1992-06-05_48_23/page/n29 | journal = Tetrahedron | date = juni 1992 | volume = 48 | issue = 23 | pages = 4687–4712 | doi = 10.1016/S0040-4020(01)81567-2 }}</ref>  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).<ref name="pmid11152419">{{cite journal | author = Battersby AR | title = Tetrapyrroles: the pigments of life | journal = Nat Prod Rep | volume = 17 | issue = 6 | pages = 507–26 |date=decembar 2000  | pmid = 11152419 | doi = 10.1039/b002635m}}</ref><ref name="pmid2664584">{{cite journal | author = Leeper FJ | title = The biosynthesis of porphyrins, chlorophylls, and vitamin B12 | journal = Nat Prod Rep | volume = 6 | issue = 2 | pages = 171–203 |date=april 1989  | pmid = 2664584 | doi = 10.1039/NP9890600171 }}</ref>

== Patologija ==

Najpoznatiji 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]].<ref>{{cite web | title = Entrez Gene: HMBS hydroxymethylbilane synthase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3145}}</ref><ref name="pmid2789372">{{cite journal |vauthors=Grandchamp B, Picat C, de Rooij F, Beaumont C, Wilson P, Deybach JC, Nordmann Y | title = A point mutation G----A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria | journal = Nucleic Acids Res. | volume = 17 | issue = 16 | pages = 6637–49 |date=august 1989  | pmid = 2789372 | pmc = 318356 | doi = 10.1093/nar/17.16.6637 }}</ref><ref name="pmid7866402">{{cite journal |vauthors=Astrin KH, Desnick RJ | title = Molecular basis of acute intermittent porphyria: mutations and polymorphisms in the human hydroxymethylbilane synthase gene | journal = Hum. Mutat. | volume = 4 | issue = 4 | pages = 243–52 | year = 1994 | pmid = 7866402 | doi = 10.1002/humu.1380040403 | s2cid = 24402776 }}</ref>

== Reference ==
{{reflist|35em}}

== Dopunska literatura ==
{{refbegin|35em}}
*{{cite journal  |vauthors=Deybach JC, Puy H |s2cid=41764609 |title=Porphobilinogen deaminase gene structure and molecular defects. |journal=J. Bioenerg. Biomembr. |volume=27 |issue= 2 |pages= 197–205 |year= 1995 |pmid= 7592566 |doi=10.1007/BF02110034  }}
*{{cite journal  |vauthors=Astrin KH, Desnick RJ |title=Molecular basis of acute intermittent porphyria: mutations and polymorphisms in the human hydroxymethylbilane synthase gene. |journal=Hum. Mutat. |volume=4 |issue= 4 |pages= 243–52 |year= 1995 |pmid= 7866402 |doi= 10.1002/humu.1380040403 |s2cid=24402776 }}
*{{cite journal   |vauthors=Helliwell JR, Nieh YP, Habash J, etal |title=Time-resolved and static-ensemble structural chemistry of hydroxymethylbilane synthase. |url=https://archive.org/details/sim_faraday-discussions_2003_122/page/131 |journal=Faraday Discussions |volume=122 |pages= 131–44; discussion 171–90 |year= 2003 |pmid= 12555854 |doi=10.1039/b201331b  |bibcode=2003FaDi..122..131H }}
*{{cite journal   |vauthors=Hessels J, Voortman G, van der Wagen A, etal |s2cid=9504522 |title=Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors. |journal=J. Inherit. Metab. Dis. |volume=27 |issue= 1 |pages= 19–27 |year= 2004 |pmid= 14970743 |doi= 10.1023/B:BOLI.0000016613.75677.05 }}
*{{cite journal  | author=Kauppinen R |s2cid=21392441 |title=Molecular diagnostics of acute intermittent porphyria. |journal=Expert Rev. Mol. Diagn. |volume=4 |issue= 2 |pages= 243–9 |year= 2004 |pmid= 14995910 |doi= 10.1586/14737159.4.2.243 }}
*{{cite journal  |vauthors=Hrdinka M, Puy H, Martasek P |title=May 2006 update in porphobilinogen deaminase gene polymorphisms and mutations causing acute intermittent porphyria: comparison with the situation in Slavic population. |journal=Physiological Research |volume=55 Suppl 2 |pages= S119–36 |year= 2007 |pmid= 17298216 }}
*{{cite journal  |vauthors=Kauppinen R, Peltonen L, Pihlaja H, Mustajoki P |title=CRIM-positive mutations of acute intermittent porphyria in Finland. |journal=Hum. Mutat. |volume=1 |issue= 5 |pages= 392–6 |year= 1993 |pmid= 1301948 |doi= 10.1002/humu.1380010508 |s2cid=10575526 }}
*{{cite journal  |vauthors=Mgone CS, Lanyon WG, Moore MR, Connor JM |s2cid=19680295 |title=Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA. |journal=Hum. Genet. |volume=90 |issue= 1–2 |pages= 12–6 |year= 1992 |pmid= 1427766 |doi=10.1007/BF00210738  }}
*{{cite journal   |vauthors=Gu XF, de Rooij F, Voortman G, etal |title=High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria |journal=Am. J. Hum. Genet. |volume=51 |issue= 3 |pages= 660–5 |year= 1992 |pmid= 1496994 | pmc=1682727  }}
*{{cite journal   |vauthors=Delfau MH, Picat C, De Rooij F, etal |title=Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease |journal=Am. J. Hum. Genet. |volume=49 |issue= 2 |pages= 421–8 |year= 1991 |pmid= 1714233 | pmc=1683312  }}
*{{cite journal   |vauthors=Namba H, Narahara K, Tsuji K, etal |title=Assignment of human porphobilinogen deaminase to 11q24.1----q24.2 by in situ hybridization and gene dosage studies |journal=Cytogenet. Cell Genet. |volume=57 |issue= 2–3 |pages= 105–8 |year= 1991 |pmid= 1914516 |doi=10.1159/000133123  }}
*{{cite journal  |vauthors=Lee JS, Anvret M |title=Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue= 23 |pages= 10912–5 |year= 1992 |pmid= 1961762 |doi=10.1073/pnas.88.23.10912  | pmc=53042  }}
*{{cite journal  |vauthors=Tunnacliffe A, McGuire RS |title=A physical linkage group in human chromosome band 11q23 covering a region implicated in leukocyte neoplasia |journal=Genomics |volume=8 |issue= 3 |pages= 447–53 |year= 1991 |pmid= 1981047 |doi=10.1016/0888-7543(90)90030-X  }}
*{{cite journal   |vauthors=Scobie GA, Llewellyn DH, Urquhart AJ, etal |s2cid=28858687 |title=Acute intermittent porphyria caused by a C----T mutation that produces a stop codon in the porphobilinogen deaminase gene |journal=Hum. Genet. |volume=85 |issue= 6 |pages= 631–4 |year= 1990 |pmid= 2227955 |doi=10.1007/BF00193588  }}
*{{cite journal   |vauthors=Delfau MH, Picat C, de Rooij FW, etal |title=Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria |journal=J. Clin. Invest. |volume=86 |issue= 5 |pages= 1511–6 |year= 1990 |pmid= 2243128 |doi=10.1172/JCI114869  | pmc=296897  }}
*{{cite journal   |vauthors=Raich N, Romeo PH, Dubart A, etal |title=Molecular cloning and complete primary sequence of human erythrocyte porphobilinogen deaminase |journal=Nucleic Acids Res. |volume=14 |issue= 15 |pages= 5955–68 |year= 1986 |pmid= 2875434 |doi=10.1093/nar/14.15.5955  | pmc=311614  }}
*{{cite journal   |vauthors=Vidaud M, Gattoni R, Stevenin J, etal |title=A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 3 |pages= 1041–5 |year= 1989 |pmid= 2915972 |doi=10.1073/pnas.86.3.1041  | pmc=286617  |bibcode=1989PNAS...86.1041V }}
{{refend}}

==Vanjski linkovi==
* [https://www.ncbi.nlm.nih.gov/books/NBK1193/  GeneReviews/NCBI/NIH/UW entry on Hydroxymethylbilane Synthase Deficiency]
* {{PDBe-KB2|P08397|Porphobilinogen deaminase}}

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[[Kategorija:EC 2.5.1]]
[[Kategorija:Geni na hromosomu 11]]
[[Kategorija:Ljudski proteini]]
[[Kategorija:Proteomika]]