PTEN

PTEN
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4O1V, 1D5R, 2KYL, 5BZX, 5BUG, 5BZZ
Identifikatori
Aliasi	PTEN
Vanjski ID-jevi	OMIM: 601728 MGI: 109583 HomoloGene: 265 GeneCards: PTEN
Lokacija gena (čovjek)
Hrom.	Hromosom 10 (čovjek)
Kraj	87,971,930 bp
Lokacija gena (miš)
Hrom.	Hromosom 19 (miš)
Kraj	32,803,560 bp
Ontologija gena
Molekularna funkcija	• phosphoprotein phosphatase activity; • phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity; • phosphatidylinositol-3-phosphatase activity; • protein serine/threonine phosphatase activity; • protein tyrosine phosphatase activity; • protein tyrosine/serine/threonine phosphatase activity; • vezivanje enzima; • platelet-derived growth factor receptor binding; • GO:0001948, GO:0016582 vezivanje za proteine; • protein kinase binding; • phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity; • anaphase-promoting complex binding; • vezivanje identičnih proteina; • hydrolase activity; • lipid binding; • ubiquitin-specific protease binding; • ionotropic glutamate receptor binding; • protein tyrosine kinase binding; • inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity; • PDZ domain binding;
Ćelijska komponenta	• citoplazma; • postsynaptic membrane; • extracellular region; • mitohondrija; • neuron projection; • cytoplasmic side of plasma membrane; • jedro; • projekcija ćelije; • dendritična kičma; • myelin sheath adaxonal region; • Schmidt-Lanterman incisure; • apical plasma membrane; • ćelijska membrana; • PML body; • nukleoplazma; • citosol; • postsynaptic cytosol;
Biološki proces	• multicellular organismal response to stress; • regulation of neuron projection development; • response to zinc ion; • positive regulation of TRAIL-activated apoptotic signaling pathway; • response to organic substance; • GO:1990376 negative regulation of G1/S transition of mitotic cell cycle; • regulation of B cell apoptotic process; • Angiogeneza; • positive regulation of ERK1 and ERK2 cascade; • negative regulation of epithelial cell proliferation; • long-term depression; • positive regulation of excitatory postsynaptic potential; • Ćelijska proliferacija; • response to ethanol; • neuron projection development; • cellular response to hypoxia; • negative regulation of cell size; • negative regulation of cell population proliferation; • prepulse inhibition; • regulation of myeloid cell apoptotic process; • male mating behavior; • locomotory behavior; • dentate gyrus development; • positive regulation of apoptotic signaling pathway; • inositol phosphate metabolic process; • response to arsenic-containing substance; • Memorija; • forebrain morphogenesis; • dendritic spine morphogenesis; • heart development; • central nervous system development; • negative regulation of axonogenesis; • regulation of cellular localization; • synapse maturation; • learning or memory; • socijalno ponašanje; • synapse assembly; • cellular response to decreased oxygen levels; • prostate gland growth; • platelet-derived growth factor receptor signaling pathway; • negative regulation of dendritic spine morphogenesis; • brain morphogenesis; • GO:0033128 negative regulation of protein phosphorylation; • regulation of cyclin-dependent protein serine/threonine kinase activity; • regulation of cellular component size; • response to nutrient; • negative regulation of synaptic vesicle clustering; • postsynaptic density assembly; • GO:0016576 protein dephosphorylation; • protein stabilization; • positive regulation of DNA-binding transcription factor activity; • negative regulation of apoptotic process; • response to glucose; • nervous system development; • adult behavior; • phosphatidylinositol dephosphorylation; • positive regulation of ubiquitin-dependent protein catabolic process; • response to inorganic substance; • canonical Wnt signaling pathway; • phosphatidylinositol biosynthetic process; • negative regulation of organ growth; • negative regulation of ribosome biogenesis; • GO:0098501, GO:0098502, GO:0006286 Defosforilacija; • locomotor rhythm; • central nervous system myelin maintenance; • regulation of axon regeneration; • response to estradiol; • response to ATP; • negative regulation of phagocytosis; • GO:1904578 response to organic cyclic compound; • protein kinase B signaling; • cardiac muscle tissue development; • lipid metabolism; • GO:0010260 starenje; • neuron-neuron synaptic transmission; • negative regulation of excitatory postsynaptic potential; • presynaptic membrane assembly; • regulation of cell cycle; • maternal behavior; • rhythmic synaptic transmission; • positive regulation of cell population proliferation; • positive regulation of apoptotic process; • negative regulation of ERK1 and ERK2 cascade; • Ćelijska migracija; • negative regulation of myelination; • inositol phosphate dephosphorylation; • regulation of synaptic transmission, GABAergic; • endothelial cell migration; • central nervous system neuron axonogenesis; • long-term potentiation; • peptidyl-tyrosine dephosphorylation; • negative regulation of axon regeneration; • negative regulation of cardiac muscle cell proliferation; • GO:0090623, GO:1903835, GO:0007092, GO:0051488, GO:0051487 positive regulation of ubiquitin protein ligase activity; • protein deubiquitination; • negative regulation of epithelial to mesenchymal transition; • negative regulation of keratinocyte migration; • cellular response to electrical stimulus; • negative regulation of wound healing, spreading of epidermal cells; • negative regulation of phosphatidylinositol 3-kinase signaling; • GO:1901313 positive regulation of gene expression; • positive regulation of cardiac muscle cell apoptotic process; • response to activity; • cellular response to insulin stimulus; • cellular response to leptin stimulus; • positive regulation of neuron differentiation; • cellular response to ethanol; • negative regulation of potassium ion transmembrane transporter activity; • cellular response to nerve growth factor stimulus; • cellular response to insulin-like growth factor stimulus; • negative regulation of signaling receptor activity; • negative regulation of protein kinase B signaling; • GO:0097285 apoptoza; • negative regulation of cell migration; • regulation of protein stability; • negative regulation of focal adhesion assembly; • negative regulation of vascular associated smooth muscle cell proliferation; • transcription initiation from RNA polymerase II promoter; • negative regulation of cyclin-dependent protein serine/threonine kinase activity; • negative regulation of neuron projection development;
	Izvori:Amigo / QuickGO
Ortolozi
	5728
	19211
	ENSG00000171862; ENSG00000284792
	ENSMUSG00000013663
	P60484
	O08586
	NM_000314; NM_001304717; NM_001304718
	NM_008960; NM_177096
	NP_000305; NP_001291646; NP_001291647; NP_000305.3
	NP_032986
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Homolog fosfataze i tenzina (PTEN) je fosfataza koja je kod ljudi kodirana genom PTEN.^[5] Mutacije ovog gena korak su u razvoju mnogih kancera, posebno glioblastoma, raka pluća, dojke i prostate. Geni koji odgovaraju PTEN-u (ortolozi)^[6] su identificirani kod većine sisara za koje su dostupni potpuni podaci o genomu.

PTEN djeluje kao gen supresije tumora, djelovanjem svog proteinskog proizvoda fosfataze. Ova fosfataza uključena je u regulaciju ćelijskog ciklusa, sprječavajući ćelije da rastu i dijele se prebrzo.^[7] Meta je mnogih lijekova protiv raka.

Protein kodiran ovim genom je fosfatidilinositol-3,4,5-trisfosfat 3-fosfataza. Sadrži domen sličan tenzinu, kao i katalitski domen sličan onom kod dvostruke specifičnosti proteiskih tiroziđn-fosfataza. Za razliku od većine proteinskih tirozin-fosfataza, ovaj protein prvenstveno defosforilira fosfoinozitidne supstrate. Negativno regulira unutarćelijske razine fosfatidilinositol-3,4,5-trisfosfata u ćelijama i funkcionira kao supresor tumora, negativnom regulacijom Akt/PKB signalnog puta.^[8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 403 aminokiseline, а molekulska težina 47.166 Da.^[9]

10	20	30	40	50
MTAIIKEIVS	RNKRRYQEDG	FDLDLTYIYP	NIIAMGFPAE	RLEGVYRNNI
DDVVRFLDSK	HKNHYKIYNL	CAERHYDTAK	FNCRVAQYPF	EDHNPPQLEL
IKPFCEDLDQ	WLSEDDNHVA	AIHCKAGKGR	TGVMICAYLL	HRGKFLKAQE
ALDFYGEVRT	RDKKGVTIPS	QRRYVYYYSY	LLKNHLDYRP	VALLFHKMMF
ETIPMFSGGT	CNPQFVVCQL	KVKIYSSNSG	PTRREDKFMY	FEFPQPLPVC
GDIKVEFFHK	QNKMLKKDKM	FHFWVNTFFI	PGPEETSEKV	ENGSLCDQEI
DSICSIERAD	NDKEYLVLTL	TKNDLDKANK	DKANRYFSPN	FKVKLYFTKT
VEEPSNPEAS	SSTSVTPDVS	DNEPDHYRYS	DTTDSDPENE	PFDEDQHTQI
TKV

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

Funkcija

Protein PTEN djeluje kao fosfataza za defosforilaciju fosfatidilinozitol (3,4,5)-trisfosfata (PtdIns (3,4,5) P₃ ili PIP₃). PTEN specifično katalizira defosforilaciju 3' fosfatnog inozitolskog prstena u PIP₃, što rezultira bifosfatnim proizvodom PIP₂ (PtdIns (4,5) P2). Ova defosforilacija je važna jer rezultira inhibicijom Akt-signalnog puta, koji ima važnu ulogu u regulaciji ćelijskog ponašanja, poput rasta, preživljavanja i migracija.

PTEN također ima slabu aktivnost proteinskih fosfataza, ali je ta aktivnost također ključna za njegovu ulogu supresora tumora. Aktivnost proteinske fosfataze PTEN -a može biti uključena u regulaciju ćelijskog ciklusa, sprječavajući ćelije da rastu i dijele se prebrzo.^[7] Bilo je mnogo prijavljenih proteinskih supstrat za PTEN, uključujući IRS1^[10] i neuređene.^[11]

PTEN je jedna od meta kandidata za lijekove kao što su onkomir i MIRN21.

Struktura

Struktura PTEN-ovog jezgra (riješeno kristalografijom rendgenskih zraka, vidi sliku u gornjem desnom uglu^[12]) otkriva da se prvenstveno sastoji od fosfataznog i C2-domena: fosfatazni domen sadrži aktivno mjesto, koje obavlja enzimsku funkciju proteina, dok C2-domen veže fosfolipidnu membranu. Tako PTEN veže membranu putem svojih domena fosfataze i C2, dovodeći aktivno mjesto na PIP₃ vezan za membranu, kako bi je defosforilirao.

Dva domena PTEN -a, tirozin-fosfatazni i C2-domen, naslijeđeni su zajedno kao jedna jedinica i stoga čine superdomen, ne samo u PTEN -u, već i u raznim drugim proteinima u gljivama, biljkama i životinjama, naprimjer, tenzinski proteini i auksilin.^[13]

Aktivno mjesto PTEN -a sastoji se od tri petlje, TI, P i petlja WPD, a sve su imenovane prema nomenklaturi PTPB1.^[12] Zajedno čine neobično dubok i širok džep, koji omogućava PTEN-u da primi glomaznu fosfatidilinozitol 3,4,5-trisfosfatmu podlogu. Smatra se da mehanizam reakcije defosforilacije PTEN-a prolazi kroz fosfoenzimski intermedijar, sa stvaranjem fosfodiesterske veze na aktivnom mjestu cisteina, C124.

U kristalnoj strukturi PTEN-a nije prisutan kratki 10-aminokiselinska nestrukturirana regija N-terminalnog domena fosfataze (od ostataka 6 do 15), poznata pod različitim imenima PIP2 vezni domen (PBD) ili PIP2 vezni motiv (PBM) ^[14]^[15]^[16] Ovo područje povećava afinitet PTEN-a za plazmamembranu vezivanjem za fosfatidilinositol 4,5-bisfosfat ili eventualno bilo koji anionski lipid.

U kristalnoj strukturi također nije prisutan unutrašnje neuređena C-terminalna regija (CTR) (obuhvata ostatke 353–403). CTR je konstitutivno fosforiliran na različitim položajima, koji utiču na različite aspekte PTEN-a, uključujući njegovu sposobnost vezanja na lipidne membrane, a djeluju i kao protein ili lipidna fosfataza.^[17]^[18]

Osim toga, PTEN se može eksprimirati i kao PTEN-L^[19] (poznat kao PTEN-Long ili PTEN-α^[20]), alternativna varijanta početnog mjesta inicijatora leucina, koja dodaje dodatne 173 aminokiseline na N-kraj PTEN-a. Tačna uloga ovog produženja aminokiselina još nije poznata, niti uzrokujuće izlučivanje PTEN-a iz ćelije ili interakciju s mitohondrijama. Predviđeno je da će produžetak N-terminala biti u velikoj mjeri poremećen,^[21] iako postoje dokazi da ima neka struktura u posljednjih dvadeset aminokiselina ekstenzije (najproksimalnije do početka PTEN -ovog metionina).^[18]

Klinički značaj

Kancer

PTEN je jedan od najčešće izgubljenih gena supresije tumora u ljudskim kancerima; u stvari, procjenjuje se da je do 70% muškaraca s rakom prostate u vrijeme postavljanja dijagnoze izgubilo kopiju gena "PTEN".^[22] Brojna istraživanja otkrila su povećanu učestalost gubitka PTEN-a u tumorima koji su jače vidljivi na dijagnostičkim snimcima kao što je mpMRI, što potencijalno odražava povećanu proliferaciju i ćelijske gustoće u ovim tumorima.^[23]

Tokom razvoja tumora dolazi do mutacija i delecija PTEN-a koje inaktiviraju njegovu enzimsku aktivnost što dovodi do povećane ćelijske proliferacije i smanjene ćelijske smrtnosti. Česta genetička inaktivacija PTEN -a javlja se kod glioblastoma, raka endometrija i raka prostate; smanjena ekspresija se nalazi u mnogim drugim tipovima tumora, poput raka pluća i dojke. Nadalje, mutacija PTEN također uzrokuje niz nasljednih predispozicija za rak.

Neokancerozna neoplazija

Identificirano je više od 70 mutacija u genu PTEN kod ljudi sa Cowdenovim sindromom. Ove mutacije se mogu promijeniti u malom broju parova baza ili, u nekim slučajevima, delecijom velikog broja parova baza. Većina ovih mutacija uzrokuje da gen PTEN pravi protein koji ne radi ispravno ili uopće ne radi. Neispravan protein ne može zaustaviti diobu črlija ili signalizirati abnormalnim ćelijama da umru, što može dovesti do rasta tumora, posebno u dojkama, štitnjači ili maternici.^[24]

Mutacije u genu "PTEN" uzrokuju nekoliko drugih poremećaja koje, poput Cowdenovog sindroma, karakterizira razvoj nekanceroznih tumora nazvanih hamartomi. Ovi poremećaji uključuju Bannayan-Riley-Ruvalcabain sindrom i sindrom sličan Proteusu. Zajedno, poremećaji uzrokovani mutacijama PTEN-a nazivaju se PTEN sindrom hamartomskog tumora ili PHTS. Mutacije odgovorne za ove sindrome uzrokuju da rezultirajući protein bude nefunkcionalan ili odsutan. Neispravan protein omogućava ćeliji da se nekontrolirano dijeli i sprječava umiranje oštećenih ćelija, što može dovesti do rasta tumora.

Funkcija mozga i autizam

Defekti gena PTEN navode se kao potencijalni uzrok poremećaja spektra autizma.^[25]

Kada je neispravan, protein PTEN stupa u interakciju s proteinom drugog gena poznatog kao Tp53, kako bi umanjio proizvodnju energije u neuronima. Ovaj teški stres dovodi do skoka štetnih promjena DNK u mitohondrijama i abnormalnih razina proizvodnje energije u malom mozgu i hipokampusu, regijama mozga koje su kritične za društveno ponašanje i spoznaju. Kada je protein PTEN nedovoljan, njegova interakcija sa p53 izaziva i nedostatke u drugim proteinima koji su takođe pronađeni kod pacijenata sa poteškoćama u učenju uključujući autizam.^[26]

Pacijenti s neispravnim PTEN-om mogu razviti lezije cerebelarne mase zvane displazijski gangliocitom ili Lhermitte-Duclosovu bolest.^[24]

Regeneracija ćelija

Snažna veza PTEN-a s inhibicijom rasta ćelija proučava se kao moguća terapijska meta u tkivima koja se obično ne regeneriraju u zrelim životinjama, poput središnjih neurona. Pokazalo se nedavno da delecijska mutacija PTEN-a^[27] dopušta regeneraciju živaca kod miševa.^[28]^[29]

Kao cilj lijekova

PTEN inhibitori

Spojevu bisperoksovanadija mogu imati neuroprotektivni učinak nakon ozljede CNS-a.^[30] PTEN ise inhibira sarkopoterijem.^[31]

Ćelijske linije

Ćelijske linije sa poznatim PTEN mutacijama uključuju:

Interakcije

Pokazano je da gen PTEN ima interakcije sa:

Također pogledajte

Sindrom multiplog hamartoma

Reference

^ ^a ^b ^c ENSG00000284792 GRCh38: Ensembl release 89: ENSG00000171862, ENSG00000284792 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000013663 - 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.
^ Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (april 1997). "Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers". Nature Genetics. 15 (4): 356–62. doi:10.1038/ng0497-356. PMID 9090379. S2CID 41286105.
^ "OrthoMaM phylogenetic marker: PTEN coding sequence". Arhivirano s originala, 27. 12. 2016. Pristupljeno 4. 9. 2021.
^ ^a ^b Chu EC, Tarnawski AS (oktobar 2004). "PTEN regulatory functions in tumor suppression and cell biology". Medical Science Monitor. 10 (10): RA235–41. PMID 15448614.
^ "Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)".
^ "UniProt, P60484". Pristupljeno 4. 9. 2021.
^ Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, Jiang X (juni 2014). "PTEN is a protein tyrosine phosphatase for IRS1". Nature Structural & Molecular Biology. 21 (6): 522–7. doi:10.1038/nsmb.2828. PMC 4167033. PMID 24814346.
^ Shnitsar I, Bashkurov M, Masson GR, Ogunjimi AA, Mosessian S, Cabeza EA, Hirsch CL, Trcka D, Gish G, Jiao J, Wu H, Winklbauer R, Williams RL, Pelletier L, Wrana JL, Barrios-Rodiles M (septembar 2015). "PTEN regulates cilia through Dishevelled". Nature Communications. 6: 8388. Bibcode:2015NatCo...6.8388S. doi:10.1038/ncomms9388. PMC 4598566. PMID 26399523.
^ ^a ^b Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (oktobar 1999). "Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association". Cell. 99 (3): 323–34. doi:10.1016/S0092-8674(00)81663-3. PMID 10555148. S2CID 5624414.
^ Haynie DT, Xue B (maj 2015). "Superdomains in the protein structure hierarchy: The case of PTP-C2". Protein Science. 24 (5): 874–82. doi:10.1002/pro.2664. PMC 4420535. PMID 25694109.
^ Campbell RB, Liu F, Ross AH (septembar 2003). "Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate". The Journal of Biological Chemistry. 278 (36): 33617–20. doi:10.1074/jbc.C300296200. PMID 12857747.
^ Iijima M, Huang YE, Luo HR, Vazquez F, Devreotes PN (april 2004). "Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis". The Journal of Biological Chemistry. 279 (16): 16606–13. doi:10.1074/jbc.M312098200. PMID 14764604.
^ McConnachie G, Pass I, Walker SM, Downes CP (maj 2003). "Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids". The Biochemical Journal. 371 (Pt 3): 947–55. doi:10.1042/BJ20021848. PMC 1223325. PMID 12534371.
^ Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN (januar 2009). "A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN". Proceedings of the National Academy of Sciences of the United States of America. 106 (2): 480–5. Bibcode:2009PNAS..106..480R. doi:10.1073/pnas.0811212106. PMC 2626728. PMID 19114656.
^ ^a ^b Masson GR, Perisic O, Burke JE, Williams RL (januar 2016). "The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity". The Biochemical Journal. 473 (2): 135–44. doi:10.1042/BJ20150931. PMC 4700475. PMID 26527737.
^ Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, Pappas K, Yu JS, Hodakoski C, Mense S, Klein J, Pegno S, Sulis ML, Goldstein H, Amendolara B, Lei L, Maurer M, Bruce J, Canoll P, Hibshoosh H, Parsons R (juli 2013). "A secreted PTEN phosphatase that enters cells to alter signaling and survival". Science. 341 (6144): 399–402. Bibcode:2013Sci...341..399H. doi:10.1126/science.1234907. PMC 3935617. PMID 23744781.
^ Liang H, He S, Yang J, Jia X, Wang P, Chen X, Zhang Z, Zou X, McNutt MA, Shen WH, Yin Y (maj 2014). "PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism". Cell Metabolism. 19 (5): 836–48. doi:10.1016/j.cmet.2014.03.023. PMC 4097321. PMID 24768297.
^ Malaney P, Uversky VN, Davé V (novembar 2013). "The PTEN Long N-tail is intrinsically disordered: increased viability for PTEN therapy". Molecular BioSystems. 9 (11): 2877–88. doi:10.1039/c3mb70267g. PMID 24056727.
^ Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (august 2005). "Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis". Nature. 436 (7051): 725–30. Bibcode:2005Natur.436..725C. doi:10.1038/nature03918. PMC 1939938. PMID 16079851.
^ Norris, Joseph M.; Simpson, Benjamin S.; Parry, Marina A.; Allen, Clare; Ball, Rhys; Freeman, Alex; Kelly, Daniel; Kim, Hyung L.; Kirkham, Alex; You, Sungyong; Kasivisvanathan, Veeru (1. 7. 2020). "Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis". European Urology Open Science (jezik: engleski). 20: 37–47. doi:10.1016/j.euros.2020.06.006. ISSN 2666-1683. PMC 7497895. PMID 33000006.
^ ^a ^b Pilarski R, Eng C (maj 2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". Journal of Medical Genetics. 41 (5): 323–6. doi:10.1136/jmg.2004.018036. PMC 1735782. PMID 15121767.
^ Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C (2012). "Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53". PLOS ONE. 7 (8): e42504. Bibcode:2012PLoSO...742504N. doi:10.1371/journal.pone.0042504. PMC 3416855. PMID 22950024.
^ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416855Ljudi s autizmom i mutacijama gena PTEN mogu imati makrocefaliju (neobično velike glave).<ref>Charney, Dennis S.; Sklar, Pamela B.; Nestler, Eric J.; Buxbaum, Joseph D. (2018). Charney & Nestler's Neurobiology of Mental Illness (jezik: engleski). Oxford University Press. str. 846. ISBN 9780190681425.
^ "Rodent of the Week: Nerves regenerated after spinal cord injury". The Los Angeles Times. 13. 8. 2010.
^ Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z (septembar 2010). "PTEN deletion enhances the regenerative ability of adult corticospinal neurons". Nature Neuroscience. 13 (9): 1075–81. doi:10.1038/nn.2603. PMC 2928871. PMID 20694004.
^ GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout
^ Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J, Xu XM (2012). "Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury". PLOS ONE. 7 (1): e30012. Bibcode:2012PLoSO...730012W. doi:10.1371/journal.pone.0030012. PMC 3254642. PMID 22253859.
^ Rozenberg K, Smirin P, Sampson SR, Rosenzweig T (august 2014). "Insulin-sensitizing and insulin-mimetic activities of Sarcopoterium spinosum extract". Journal of Ethnopharmacology. 155 (1): 362–72. doi:10.1016/j.jep.2014.05.030. PMID 24882728.
^ ^a ^b Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (mart 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–7. doi:10.1126/science.275.5308.1943. PMID 9072974. S2CID 23093929.
^ ^a ^b Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG (septembar 2002). "Direct identification of PTEN phosphorylation sites". FEBS Letters. 528 (1–3): 145–53. doi:10.1016/S0014-5793(02)03274-X. PMID 12297295. S2CID 1093672.
^ Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, Lasky LA (juli 2000). "Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase". The Journal of Biological Chemistry. 275 (28): 21477–85. doi:10.1074/jbc.M909741199. PMID 10748157.
^ Yu Z, Fotouhi-Ardakani N, Wu L, Maoui M, Wang S, Banville D, Shen SH (oktobar 2002). "PTEN associates with the vault particles in HeLa cells". The Journal of Biological Chemistry. 277 (43): 40247–52. doi:10.1074/jbc.M207608200. PMID 12177006.
^ Wang X, Shi Y, Wang J, Huang G, Jiang X (septembar 2008). "Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation". The Biochemical Journal. 414 (2): 221–9. doi:10.1042/BJ20080674. PMID 18498243.
^ Lin HK, Hu YC, Lee DK, Chang C (oktobar 2004). "Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells". Molecular Endocrinology. 18 (10): 2409–23. doi:10.1210/me.2004-0117. PMID 15205473.
^ Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H (februar 2003). "PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms". Cancer Cell. 3 (2): 117–30. doi:10.1016/S1535-6108(03)00021-7. PMID 12620407.
^ Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (juli 1999). "PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway". The Journal of Biological Chemistry. 274 (29): 20693–703. doi:10.1074/jbc.274.29.20693. PMID 10400703.
^ Haier J, Nicolson GL (februar 2002). "PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow". Oncogene. 21 (9): 1450–60. doi:10.1038/sj.onc.1205213. PMID 11857088.

Dopunska literatura

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (mart 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–7. doi:10.1126/science.275.5308.1943. PMID 9072974. S2CID 23093929.
Simpson L, Parsons R (mart 2001). "PTEN: life as a tumor suppressor". Experimental Cell Research. 264 (1): 29–41. doi:10.1006/excr.2000.5130. PMID 11237521.
Eng C (septembar 2003). "PTEN: one gene, many syndromes". Human Mutation. 22 (3): 183–98. doi:10.1002/humu.10257. PMID 12938083. S2CID 13417857.
Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, Sasaki J, Yajima N, Horie Y, Hasegawa G, Naito M, Miyazaki J, Suda T, Itoh H, Nakao K, Mak TW, Nakano T, Suzuki A (septembar 2005). "The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis". Genes & Development. 19 (17): 2054–65. doi:10.1101/gad.1308805. PMC 1199575. PMID 16107612.
Leslie NR, Downes CP (august 2004). "PTEN function: how normal cells control it and tumour cells lose it". The Biochemical Journal. 382 (Pt 1): 1–11. doi:10.1042/BJ20040825. PMC 1133909. PMID 15193142.
Sansal I, Sellers WR (juli 2004). "The biology and clinical relevance of the PTEN tumor suppressor pathway". Journal of Clinical Oncology. 22 (14): 2954–63. doi:10.1200/JCO.2004.02.141. PMID 15254063.
Waite KA, Eng C (april 2002). "Protean PTEN: form and function". American Journal of Human Genetics. 70 (4): 829–44. doi:10.1086/340026. PMC 379112. PMID 11875759.
Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C (august 2003). "Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway". American Journal of Human Genetics. 73 (2): 404–11. doi:10.1086/377109. PMC 1180378. PMID 12844284.
Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L, Wan Q, Backstrom JR, Zhang X (mart 2006). "Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse". Nature Medicine. 12 (3): 324–9. doi:10.1038/nm1349. PMID 16474401. S2CID 22093776.

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
PTEN Protein na US National Library of Medicine Medical Subject Headings (MeSH)
"PTEN Gene - phosphatase and tensin homolog". GeneCards. The Weizmann Institute of Science. Arhivirano s originala, 8. 10. 2007. Pristupljeno 12. 3. 2009.
"Gene overview of all published AD-association studies for PTEN". Alzforum: AlzGene. Alzheimer Research Forum. Arhivirano s originala, 10. 2. 2009. Pristupljeno 12. 3. 2009.
Research shows gene defect's role in autism-like behavior
Dance Your PhD 2017 : A Story of Tumor Suppression Deepti Mathur. PTEN and cancer explained in dance. A metabolic pathway uses glutamine to create a component of DNA. This pathway is regulated in part by PTEN. Loss of PTEN allows the pathway to go into overdrive, leading to cancer. A drug that interrupts the PTEN pathway preferentially destroys cancer cells.
PDBe-KB provides an overview of all the structure information available in the PDB for Human Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

[refGRCh38Ensembl-1] ENSG00000284792 GRCh38: Ensembl release 89: ENSG00000171862, ENSG00000284792 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000013663 - 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.

[pmid9090379-5] Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (april 1997). "Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers". Nature Genetics. 15 (4): 356–62. doi:10.1038/ng0497-356. PMID 9090379. S2CID 41286105.

[OrthoMaM-6] "OrthoMaM phylogenetic marker: PTEN coding sequence". Arhivirano s originala, 27. 12. 2016. Pristupljeno 4. 9. 2021.

[pmid15448614-7] Chu EC, Tarnawski AS (oktobar 2004). "PTEN regulatory functions in tumor suppression and cell biology". Medical Science Monitor. 10 (10): RA235–41. PMID 15448614.

[8] "Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)".

[UniProt-9] "UniProt, P60484". Pristupljeno 4. 9. 2021.

[10] Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, Jiang X (juni 2014). "PTEN is a protein tyrosine phosphatase for IRS1". Nature Structural & Molecular Biology. 21 (6): 522–7. doi:10.1038/nsmb.2828. PMC 4167033. PMID 24814346.

[11] Shnitsar I, Bashkurov M, Masson GR, Ogunjimi AA, Mosessian S, Cabeza EA, Hirsch CL, Trcka D, Gish G, Jiao J, Wu H, Winklbauer R, Williams RL, Pelletier L, Wrana JL, Barrios-Rodiles M (septembar 2015). "PTEN regulates cilia through Dishevelled". Nature Communications. 6: 8388. Bibcode:2015NatCo...6.8388S. doi:10.1038/ncomms9388. PMC 4598566. PMID 26399523.

[pmid10555148-12] Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (oktobar 1999). "Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association". Cell. 99 (3): 323–34. doi:10.1016/S0092-8674(00)81663-3. PMID 10555148. S2CID 5624414.

[13] Haynie DT, Xue B (maj 2015). "Superdomains in the protein structure hierarchy: The case of PTP-C2". Protein Science. 24 (5): 874–82. doi:10.1002/pro.2664. PMC 4420535. PMID 25694109.

[14] Campbell RB, Liu F, Ross AH (septembar 2003). "Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate". The Journal of Biological Chemistry. 278 (36): 33617–20. doi:10.1074/jbc.C300296200. PMID 12857747.

[15] Iijima M, Huang YE, Luo HR, Vazquez F, Devreotes PN (april 2004). "Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis". The Journal of Biological Chemistry. 279 (16): 16606–13. doi:10.1074/jbc.M312098200. PMID 14764604.

[16] McConnachie G, Pass I, Walker SM, Downes CP (maj 2003). "Interfacial kinetic analysis of the tumour suppressor phosphatase, PTEN: evidence for activation by anionic phospholipids". The Biochemical Journal. 371 (Pt 3): 947–55. doi:10.1042/BJ20021848. PMC 1223325. PMID 12534371.

[17] Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN (januar 2009). "A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN". Proceedings of the National Academy of Sciences of the United States of America. 106 (2): 480–5. Bibcode:2009PNAS..106..480R. doi:10.1073/pnas.0811212106. PMC 2626728. PMID 19114656.

[:0-18] Masson GR, Perisic O, Burke JE, Williams RL (januar 2016). "The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity". The Biochemical Journal. 473 (2): 135–44. doi:10.1042/BJ20150931. PMC 4700475. PMID 26527737.

[19] Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, Pappas K, Yu JS, Hodakoski C, Mense S, Klein J, Pegno S, Sulis ML, Goldstein H, Amendolara B, Lei L, Maurer M, Bruce J, Canoll P, Hibshoosh H, Parsons R (juli 2013). "A secreted PTEN phosphatase that enters cells to alter signaling and survival". Science. 341 (6144): 399–402. Bibcode:2013Sci...341..399H. doi:10.1126/science.1234907. PMC 3935617. PMID 23744781.

[20] Liang H, He S, Yang J, Jia X, Wang P, Chen X, Zhang Z, Zou X, McNutt MA, Shen WH, Yin Y (maj 2014). "PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism". Cell Metabolism. 19 (5): 836–48. doi:10.1016/j.cmet.2014.03.023. PMC 4097321. PMID 24768297.

[21] Malaney P, Uversky VN, Davé V (novembar 2013). "The PTEN Long N-tail is intrinsically disordered: increased viability for PTEN therapy". Molecular BioSystems. 9 (11): 2877–88. doi:10.1039/c3mb70267g. PMID 24056727.

[pmid16079851-22] Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (august 2005). "Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis". Nature. 436 (7051): 725–30. Bibcode:2005Natur.436..725C. doi:10.1038/nature03918. PMC 1939938. PMID 16079851.

[23] Norris, Joseph M.; Simpson, Benjamin S.; Parry, Marina A.; Allen, Clare; Ball, Rhys; Freeman, Alex; Kelly, Daniel; Kim, Hyung L.; Kirkham, Alex; You, Sungyong; Kasivisvanathan, Veeru (1. 7. 2020). "Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis". European Urology Open Science (jezik: engleski). 20: 37–47. doi:10.1016/j.euros.2020.06.006. ISSN 2666-1683. PMC 7497895. PMID 33000006.

[JMG1-24] Pilarski R, Eng C (maj 2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". Journal of Medical Genetics. 41 (5): 323–6. doi:10.1136/jmg.2004.018036. PMC 1735782. PMID 15121767.

[25] Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C (2012). "Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53". PLOS ONE. 7 (8): e42504. Bibcode:2012PLoSO...742504N. doi:10.1371/journal.pone.0042504. PMC 3416855. PMID 22950024.

[pmid22950024-26] ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416855Ljudi s autizmom i mutacijama gena PTEN mogu imati makrocefaliju (neobično velike glave).<ref>Charney, Dennis S.; Sklar, Pamela B.; Nestler, Eric J.; Buxbaum, Joseph D. (2018). Charney & Nestler's Neurobiology of Mental Illness (jezik: engleski). Oxford University Press. str. 846. ISBN 9780190681425.

[27] "Rodent of the Week: Nerves regenerated after spinal cord injury". The Los Angeles Times. 13. 8. 2010.

[pmid20694004-28] Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z (septembar 2010). "PTEN deletion enhances the regenerative ability of adult corticospinal neurons". Nature Neuroscience. 13 (9): 1075–81. doi:10.1038/nn.2603. PMC 2928871. PMID 20694004.

[29] GSK3-CRMP2 signaling mediates axonal regeneration induced by Pten knockout

[Walker2012-30] Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J, Xu XM (2012). "Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury". PLOS ONE. 7 (1): e30012. Bibcode:2012PLoSO...730012W. doi:10.1371/journal.pone.0030012. PMC 3254642. PMID 22253859.

[pmid24882728-31] Rozenberg K, Smirin P, Sampson SR, Rosenzweig T (august 2014). "Insulin-sensitizing and insulin-mimetic activities of Sarcopoterium spinosum extract". Journal of Ethnopharmacology. 155 (1): 362–72. doi:10.1016/j.jep.2014.05.030. PMID 24882728.

[pmid9072974-32] Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (mart 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–7. doi:10.1126/science.275.5308.1943. PMID 9072974. S2CID 23093929.

[pmid12297295-33] Miller SJ, Lou DY, Seldin DC, Lane WS, Neel BG (septembar 2002). "Direct identification of PTEN phosphorylation sites". FEBS Letters. 528 (1–3): 145–53. doi:10.1016/S0014-5793(02)03274-X. PMID 12297295. S2CID 1093672.

[pmid10748157-34] Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, Lasky LA (juli 2000). "Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase". The Journal of Biological Chemistry. 275 (28): 21477–85. doi:10.1074/jbc.M909741199. PMID 10748157.

[pmid12177006-35] Yu Z, Fotouhi-Ardakani N, Wu L, Maoui M, Wang S, Banville D, Shen SH (oktobar 2002). "PTEN associates with the vault particles in HeLa cells". The Journal of Biological Chemistry. 277 (43): 40247–52. doi:10.1074/jbc.M207608200. PMID 12177006.

[pmid18498243-36] Wang X, Shi Y, Wang J, Huang G, Jiang X (septembar 2008). "Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation". The Biochemical Journal. 414 (2): 221–9. doi:10.1042/BJ20080674. PMID 18498243.

[pmid15205473-37] Lin HK, Hu YC, Lee DK, Chang C (oktobar 2004). "Regulation of androgen receptor signaling by PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor through distinct mechanisms in prostate cancer cells". Molecular Endocrinology. 18 (10): 2409–23. doi:10.1210/me.2004-0117. PMID 15205473.

[pmid12620407-38] Freeman DJ, Li AG, Wei G, Li HH, Kertesz N, Lesche R, Whale AD, Martinez-Diaz H, Rozengurt N, Cardiff RD, Liu X, Wu H (februar 2003). "PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms". Cancer Cell. 3 (2): 117–30. doi:10.1016/S1535-6108(03)00021-7. PMID 12620407.

[pmid10400703-39] Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (juli 1999). "PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway". The Journal of Biological Chemistry. 274 (29): 20693–703. doi:10.1074/jbc.274.29.20693. PMID 10400703.

[pmid11857088-40] Haier J, Nicolson GL (februar 2002). "PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow". Oncogene. 21 (9): 1450–60. doi:10.1038/sj.onc.1205213. PMID 11857088.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

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[12]

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[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

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p r u Enzimi
Teme	Aktivno mjesto Alosterna regulacija Difuzijski limitirani enzim EC broj Enzimska kataliza Inhibicija enzimskih reakcija Kinetika enzima Koenzim Kooperativnost Lineweaver–Burkov dijagram Michaelis–Mentenova kinetika Mjesto vezanja Spisak enzima
Tipovi	EC1 Oksidoreduktaze/spisak EC2 Transferaze/spisak EC3 Hidrolaze/spisak EC4 Lijaze/spisak EC5 Izomeraze/spisak EC6 Ligaze/spisak