GALT

C-terminalni domen galaktoza-1-fosfat uridil-transferaze
C-terminalni domen galaktoza-1-fosfat uridil-transferaze
	Struktura nukleotidiltransferaze kompleksirane sa UDP-galaktozom
Identifikatori
Simbol	GalP_UDP_tr_C

N-terminalni domen galaktoza-1-fosfat uridil-transferaze
N-terminalni domen galaktoza-1-fosfat uridil-transferaze
Identifikatori
Simbol	GalP_UDP_transf

GALT
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	5IN3
Identifikatori
Aliasi	GALT
Vanjski ID-jevi	OMIM: 606999 MGI: 95638 HomoloGene: 126 GeneCards: GALT
Lokacija gena (čovjek)
Hrom.	Hromosom 9 (čovjek)
Kraj	34,651,035 bp
Lokacija gena (miš)
Hrom.	Hromosom 4 (miš)
Kraj	41,758,695 bp
Ontologija gena
Molekularna funkcija	• aktivnost sa transferazom; • nucleotidyltransferase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje iona metala; • UDP-glucose:hexose-1-phosphate uridylyltransferase activity; • vezivanje iona cinka;
Ćelijska komponenta	• citosol; • Golđijev aparat; • citoplazma;
Biološki proces	• UDP-glucose catabolic process; • galactose catabolic process; • galactose catabolic process via UDP-galactose; • UDP-glucose metabolic process; • galactose metabolic process; • carbohydrate metabolic process;
	Izvori:Amigo / QuickGO
Ortolozi
	2592
	14430
	ENSG00000213930
	ENSMUSG00000036073
	P07902
	Q03249
	NM_001258332; NM_000155; NM_147131; NM_147132
	NM_016658; NM_001302511
	NP_000146; NP_001245261
NP_001289440; NP_057867; NP_001356064; NP_001356069; NP_001356070;
	NP_001356071; NP_001356072; NP_001356073; NP_001356076; NP_001382559
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Galaktoza-1-fosfat uridililtransferaza – GALT ili G1PUT – je enzim (EC 2.7.7.12) odgovoran za pretvaranje unesene galaktoze u glukozu.^[5]

Galaktoza-1-fosfat uridilililtransferaza (GALT) katalizira drugi korak Leloir puta metabolizma galaktoze:

UDP-glukoza + galaktoza 1-fosfat

\rightleftharpoons

glukoza 1-fosfat + UDP-galaktoza

Ekspresija GALT -a kontrolira se djelovanjem gena FOXO3. Nedostatak ovog enzima dovodi do klasične galaktozemije kod ljudi i može biti smrtonosan u dobi novorođenčadi ako se laktoza ne ukloni iz prehrane. Patofiziologija galaktozemije nije jasno definirana.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 379 aminokiselina, а molekulska težina 43.363 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MSRSGTDPQQ	RQQASEADAA	AATFRANDHQ	HIRYNPLQDE	WVLVSAHRMK
RPWQGQVEPQ	LLKTVPRHDP	LNPLCPGAIR	ANGEVNPQYD	STFLFDNDFP
ALQPDAPSPG	PSDHPLFQAK	SARGVCKVMC	FHPWSDVTLP	LMSVPEIRAV
VDAWASVTEE	LGAQYPWVQI	FENKGAMMGC	SNPHPHCQVW	ASSFLPDIAQ
REERSQQAYK	SQHGEPLLME	YSRQELLRKE	RLVLTSEHWL	VLVPFWATWP
YQTLLLPRRH	VRRLPELTPA	ERDDLASIMK	KLLTKYDNLF	ETSFPYSMGW
HGAPTGSEAG	ANWNHWQLHA	HYYPPLLRSA	TVRKFMVGYE	MLAQAQRDLT
PEQAAERLRA	LPEVHYHLGQ	KDRETATIA

Strukturne studije

Trodimenzijsku strukturu pri rezoluciji 180 pm (kristalografija rendgenskih zraka) GALT-a odredili su Wedekind, Frey i Rayment, a njihovom strukturnom analizom utvrđeno je da su ključne aminokiseline bitne za funkciju GALT. Među njima su Leu4, Phe75, Asn77, Asp78, Phe79 i Val108, koji su u skladu s ostacima koji su uključeni, kako u eksperimente s tačkastom mutacijom, tako i u klinički skrining koji imaju ulogu u ljudskoj galaktozemiji.^[7]

Mehanizam

GALT katalizira drugu reakciju Leloirovog puta metabolizma galaktoze, kinetikom modela ping pong bi-bi, mehanizmom dvostruki pomak.^[8] To znači da se neto reakcija sastoji od dva reaktanta i dva produkta (vidi gore navedenu reakciju), a odvija se prema sljedećem mehanizmu: enzim reagira s jednim supstratom, stvarajući jedan proizvod i modificirani enzim, koji nastavlja reagirati s drugim supstrata za stvaranje drugog proizvoda, uz regeneraciju izvornog enzima.^[9] U slučaju GALT-a, ostatak His166 djeluje kao moćan nukleofil kako bi olakšao prijenos nukleotida između UDP-heksoza i heksoza-1-fosfata.^[10]

UDP-glukoza + E-His $\rightleftharpoons$ glukoza-1-fosfat + E-His-UMP
Galaktoza-1-fosfat + E-His-UMP $\rightleftharpoons$ UDP-galaktoza + E-His^[10]

Dvostepeno djelovanje galaktoza-1-fosfat uridililtransferaze. Slika prema:^[11]

Klinički značaj

Nedostatak GALT uzrokuje klasičnu galaktozemiju. Galaktozemija je autosomno recesivni nasljedni poremećaj koji se može otkriti kod novorođenčadi i u djetinjstvu.^[12] Javlja se otprilike 1/40.000 – 60.000 živorođene djece. Klasična galaktozemija (G/G) uzrokovana je nedostatkom GALT aktivnosti, dok su češće kliničke manifestacije, Nedostatak galaktoza-1-fosfat uridililtransferaze Duarte (D/D) i Duarte/klasična varijanta (D/G) uzrokovane su slabljenjem aktivnosti GALT-a.^[13] Simptomi uključuju otkazivanje jajnika, razvojni poremećaj koordinacije (poteškoće u korektnom i konzistentnom govoru),^[14] i nervne nedostatke.^[13] Jedna mutacija u bilo kojem od nekoliko parova baza može dovesti do nedostatka aktivnosti GALT-a.^[15] Naprimjer, jedna mutacija iz A u G u egzonu 6 gena GALT mijenja Glu188 u arginin, a mutacija iz A u G u egzonu 10 pretvara Asn314 u aspartat.^[13] Ove dvije mutacije također dodaju nova rezna mjesta restrikcijskih enzima, koja omogućuju detekciju i opsežni skrining populacije pomoću PCR-a (lančana reakcija polimeraze).^[13] Skriningom je uglavnom eliminirana neonatusna smrt uzrokovana G /G galaktozemijom, ali je bolest, zbog uloge GALT-a u biohemijskom metabolizmu unesene galaktoze (koja je otrovna pri akumulaciji) energetski korisna glukoza, svakako može biti smrtonosna.^[12]^[16] Međutim, oboljeli od galaktozemije mogu živjeti relativno normalnim životom izbjegavajući mliječne proizvode i bilo što drugo što sadrži galaktozu (jer se ne može metabolizirati), ali još uvijek postoji potencijal za probleme u neurološkom razvoju ili druge komplikacije, čak i kod onih koji izbjegavaju galaktozu.^[17]

Baza podataka bolesti

Galactosemia (GALT) Mutation Database

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000213930 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000036073 - 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.
^ ^a ^b "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase".
^ "UniProt, P07902". Pristupljeno 8. 9. 2021.
^ Seyrantepe V, Ozguc M, Coskun T, Ozalp I, Reichardt JK (1999). "Identification of mutations in the galactose-1-phosphate uridyltransferase (GALT) gene in 16 Turkish patients with galactosemia, including a novel mutation of F294Y. Mutation in brief no. 235. Online". Human Mutation. 13 (4): 339. doi:10.1002/(SICI)1098-1004(1999)13:4<339::AID-HUMU18>3.0.CO;2-S. PMID 10220154.
^ Wong LJ, Frey PA (septembar 1974). "Galactose-1-phosphate uridylyltransferase: rate studies confirming a uridylyl-enzyme intermediate on the catalytic pathway". Biochemistry. 13 (19): 3889–94. doi:10.1021/bi00716a011. PMID 4606575.
^ "Archived copy". Arhivirano s originala, 3. 3. 2016. Pristupljeno 19. 5. 2010.CS1 održavanje: arhivirana kopija u naslovu (link)
^ ^a ^b Wedekind JE, Frey PA, Rayment I (septembar 1995). "Three-dimensional structure of galactose-1-phosphate uridylyltransferase from Escherichia coli at 1.8 A resolution". Biochemistry. 34 (35): 11049–61. doi:10.1021/bi00035a010. PMID 7669762.
^ "Archived copy". Arhivirano s originala, 4. 12. 2008. Pristupljeno 19. 5. 2010.CS1 održavanje: arhivirana kopija u naslovu (link)
^ ^a ^b Fridovich-Keil JL (decembar 2006). "Galactosemia: the good, the bad, and the unknown". Journal of Cellular Physiology. 209 (3): 701–5. doi:10.1002/jcp.20820. PMID 17001680. S2CID 32233614.
^ ^a ^b ^c ^d Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP (1995). "A molecular approach to galactosemia". European Journal of Pediatrics. 154 (7 Suppl 2): S21-7. doi:10.1007/BF02143798. PMID 7671959. S2CID 11937698.
^ "Archived copy". Arhivirano s originala, 28. 2. 2006. Pristupljeno 19. 5. 2010.CS1 održavanje: arhivirana kopija u naslovu (link)
^ Dobrowolski SF, Banas RA, Suzow JG, Berkley M, Naylor EW (februar 2003). "Analysis of common mutations in the galactose-1-phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia". The Journal of Molecular Diagnostics. 5 (1): 42–7. doi:10.1016/S1525-1578(10)60450-3. PMC 1907369. PMID 12552079.
^ Lai K, Elsas LJ, Wierenga KJ (novembar 2009). "Galactose toxicity in animals". IUBMB Life. 61 (11): 1063–74. doi:10.1002/iub.262. PMC 2788023. PMID 19859980.
^ "Arhivirana kopija". Arhivirano s originala, 29. 5. 2013. Pristupljeno 8. 9. 2021.CS1 održavanje: arhivirana kopija u naslovu (link)

Dopunska literatura

Reichardt JK (1993). "Genetic basis of galactosemia". Human Mutation. 1 (3): 190–6. doi:10.1002/humu.1380010303. PMID 1301925. S2CID 504197.
Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD (1999). "Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene". Human Mutation. 13 (6): 417–30. doi:10.1002/(SICI)1098-1004(1999)13:6<417::AID-HUMU1>3.0.CO;2-0. PMID 10408771.
Reichardt JK, Belmont JW, Levy HL, Woo SL (mart 1992). "Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia". Genomics. 12 (3): 596–600. doi:10.1016/0888-7543(92)90453-Y. PMID 1373122.
Leslie ND, Immerman EB, Flach JE, Florez M, Fridovich-Keil JL, Elsas LJ (oktobar 1992). "The human galactose-1-phosphate uridyltransferase gene". Genomics. 14 (2): 474–80. doi:10.1016/S0888-7543(05)80244-7. PMID 1427861.
Reichardt JK, Levy HL, Woo SL (juni 1992). "Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase". Biochemistry. 31 (24): 5430–3. doi:10.1021/bi00139a002. PMID 1610789.
Reichardt JK, Packman S, Woo SL (oktobar 1991). "Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase". American Journal of Human Genetics. 49 (4): 860–7. PMC 1683190. PMID 1897530.
Reichardt JK, Woo SL (april 1991). "Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase". Proceedings of the National Academy of Sciences of the United States of America. 88 (7): 2633–7. Bibcode:1991PNAS...88.2633R. doi:10.1073/pnas.88.7.2633. PMC 51292. PMID 2011574.
Flach JE, Reichardt JK, Elsas LJ (august 1990). "Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase". Molecular Biology & Medicine. 7 (4): 365–9. PMID 2233247.
Reichardt JK, Berg P (april 1988). "Cloning and characterization of a cDNA encoding human galactose-1-phosphate uridyl transferase". Molecular Biology & Medicine. 5 (2): 107–22. PMID 2840550.
Bergren WG, Donnell GN (juli 1973). "A new variant of galactose-1-phosphate uridyltransferase in man: the Los Angeles variant". Annals of Human Genetics. 37 (1): 1–8. doi:10.1111/j.1469-1809.1973.tb01808.x. PMID 4759900. S2CID 22699183.
Shih LY, Suslak L, Rosin I, Searle BM, Desposito F (novembar 1984). "Gene dosage studies supporting localization of the structural gene for galactose-1-phosphate uridyl transferase (GALT) to band p13 of chromosome 9". American Journal of Medical Genetics. 19 (3): 539–43. doi:10.1002/ajmg.1320190316. PMID 6095663.
Ashino J, Okano Y, Suyama I, Yamazaki T, Yoshino M, Furuyama J, Lin HC, Reichardt JK, Isshiki G (1995). "Molecular characterization of galactosemia (type 1) mutations in Japanese". Human Mutation. 6 (1): 36–43. doi:10.1002/humu.1380060108. PMID 7550229. S2CID 23500152.
Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP (1995). "A molecular approach to galactosemia". European Journal of Pediatrics. 154 (7 Suppl 2): S21-7. doi:10.1007/BF02143798. PMID 7671959. S2CID 11937698.
Elsas LJ, Langley S, Steele E, Evinger J, Fridovich-Keil JL, Brown A, Singh R, Fernhoff P, Hjelm LN, Dembure PP (mart 1995). "Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes". American Journal of Human Genetics. 56 (3): 630–9. PMC 1801164. PMID 7887416.
Fridovich-Keil JL, Langley SD, Mazur LA, Lennon JC, Dembure PP, Elsas JL (mart 1995). "Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family". American Journal of Human Genetics. 56 (3): 640–6. PMC 1801186. PMID 7887417.
Davit-Spraul A, Pourci ML, Ng KH, Soni T, Lemonnier A (novembar 1994). "Regulatory effects of galactose on galactose-1-phosphate uridyltransferase activity on human hepatoblastoma HepG2 cells". FEBS Letters. 354 (2): 232–6. doi:10.1016/0014-5793(94)01133-8. PMID 7957929. S2CID 45242645.
Lin HC, Kirby LT, Ng WG, Reichardt JK (februar 1994). "On the molecular nature of the Duarte variant of galactose-1-phosphate uridyl transferase (GALT)". Human Genetics. 93 (2): 167–9. doi:10.1007/BF00210604. PMID 8112740. S2CID 42558872.
Elsas LJ, Dembure PP, Langley S, Paulk EM, Hjelm LN, Fridovich-Keil J (juni 1994). "A common mutation associated with the Duarte galactosemia allele". American Journal of Human Genetics. 54 (6): 1030–6. PMC 1918187. PMID 8198125.
Reichardt JK, Novelli G, Dallapiccola B (mart 1993). "Molecular characterization of the H319Q galactosemia mutation". Human Molecular Genetics. 2 (3): 325–6. doi:10.1093/hmg/2.3.325. PMID 8499924.

Vanjski linkovi

Galactose-1-P-Uridyltransferase na US National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NIH/NCBI/UW entry on Galactosemia
Galactosemia (GALT) Mutation Database
GALT Protein Database Arhivirano 9. 11. 2012. na Wayback Machine
PDBe-KB provides an overview of all the structure information available in the PDB for Human Galactose-1-phosphate uridylyltransferase

Šablon:Metabolizam fruktoze i galaktoze

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000213930 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000036073 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase".

[UniProt-6] "UniProt, P07902". Pristupljeno 8. 9. 2021.

[mutations-7] Seyrantepe V, Ozguc M, Coskun T, Ozalp I, Reichardt JK (1999). "Identification of mutations in the galactose-1-phosphate uridyltransferase (GALT) gene in 16 Turkish patients with galactosemia, including a novel mutation of F294Y. Mutation in brief no. 235. Online". Human Mutation. 13 (4): 339. doi:10.1002/(SICI)1098-1004(1999)13:4<339::AID-HUMU18>3.0.CO;2-S. PMID 10220154.

[test-8] Wong LJ, Frey PA (septembar 1974). "Galactose-1-phosphate uridylyltransferase: rate studies confirming a uridylyl-enzyme intermediate on the catalytic pathway". Biochemistry. 13 (19): 3889–94. doi:10.1021/bi00716a011. PMID 4606575.

[bibi-9] "Archived copy". Arhivirano s originala, 3. 3. 2016. Pristupljeno 19. 5. 2010.CS1 održavanje: arhivirana kopija u naslovu (link)

[structure-10] Wedekind JE, Frey PA, Rayment I (septembar 1995). "Three-dimensional structure of galactose-1-phosphate uridylyltransferase from Escherichia coli at 1.8 A resolution". Biochemistry. 34 (35): 11049–61. doi:10.1021/bi00035a010. PMID 7669762.

[pic-11] "Archived copy". Arhivirano s originala, 4. 12. 2008. Pristupljeno 19. 5. 2010.CS1 održavanje: arhivirana kopija u naslovu (link)

[Frido-12] Fridovich-Keil JL (decembar 2006). "Galactosemia: the good, the bad, and the unknown". Journal of Cellular Physiology. 209 (3): 701–5. doi:10.1002/jcp.20820. PMID 17001680. S2CID 32233614.

[Elsas_1995-13] Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP (1995). "A molecular approach to galactosemia". European Journal of Pediatrics. 154 (7 Suppl 2): S21-7. doi:10.1007/BF02143798. PMID 7671959. S2CID 11937698.

[apraxia-14] "Archived copy". Arhivirano s originala, 28. 2. 2006. Pristupljeno 19. 5. 2010.CS1 održavanje: arhivirana kopija u naslovu (link)

[Dob-15] Dobrowolski SF, Banas RA, Suzow JG, Berkley M, Naylor EW (februar 2003). "Analysis of common mutations in the galactose-1-phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia". The Journal of Molecular Diagnostics. 5 (1): 42–7. doi:10.1016/S1525-1578(10)60450-3. PMC 1907369. PMID 12552079.

[lethal-16] Lai K, Elsas LJ, Wierenga KJ (novembar 2009). "Galactose toxicity in animals". IUBMB Life. 61 (11): 1063–74. doi:10.1002/iub.262. PMC 2788023. PMID 19859980.

[med-17] "Arhivirana kopija". Arhivirano s originala, 29. 5. 2013. Pristupljeno 8. 9. 2021.CS1 održavanje: arhivirana kopija u naslovu (link)

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