pseudoenzyme
{{Short description|Catalytically deficient enzymes}}
Pseudoenzymes are variants of enzymes that are catalytically-deficient (usually inactive), meaning that they perform little or no enzyme catalysis. {{cite journal | vauthors = Ribeiro AJ, Das S, Dawson N, Zaru R, Orchard S, Thornton JM, Orengo C, Zeqiraj E, Murphy JM, Eyers PA| title = Emerging concepts in pseudoenzyme classification, evolution, and signaling | journal = Science Signaling | volume = 12 | issue = 594 | pages = eaat9797 | date = Aug 2019 | pmid = 31409758 | doi = 10.1126/scisignal.aat9797 | doi-access = }} They are believed to be represented in all major enzyme families in the kingdoms of life, where they have important signaling and metabolic functions, many of which are only now coming to light.{{cite journal | vauthors = Kwon A, Scott S, Taujale R, Yeung W, Kochut KJ, Eyers PA, Kannan N| title = Tracing the origin and evolution of pseudokinases across the tree of life | journal = Science Signaling | volume = 12 | issue = 578 | pages = eaav3810 | date = April 2019 | pmid = 31015289 | doi = 10.1126/scisignal.aav3810 | pmc = 6997932 }} Pseudoenzymes are becoming increasingly important to analyse, especially as the bioinformatic analysis of genomes reveals their ubiquity. Their important regulatory and sometimes disease-associated functions in metabolic and signalling pathways are also shedding new light on the non-catalytic functions of active enzymes, of moonlighting proteins,{{cite journal | vauthors = Jeffery CJ | title = The demise of catalysis, but new functions arise: pseudoenzymes as the phoenixes of the protein world | journal = Biochemical Society Transactions | volume = 47 | issue = 1 | pages = 371–379 | date = Feb 2019 | pmid = 30710059 | doi = 10.1042/BST20180473 | s2cid = 73437705 | url = https://figshare.com/articles/journal_contribution/10770689 }}{{cite journal | vauthors = Jeffery CJ | title = Multitalented actors inside and outside the cell: recent discoveries add to the number of moonlighting proteins | journal = Biochemical Society Transactions | volume = 47 | issue = 6 | pages = 1941–1948 | date = Dec 2019 | pmid = 31803903 | doi = 10.1042/BST20190798 | s2cid = 208643133 }} the re-purposing of proteins in distinct cellular roles (Protein moonlighting). They are also suggesting new ways to target and interpret cellular signalling mechanisms using small molecules and drugs.{{cite journal | vauthors = Eyers PA, Murphy JM | title = The evolving world of pseudoenzymes: proteins, prejudice and zombies | journal = BMC Biology | volume = 14 | issue = 1 | pages = 98 | date = November 2016 | pmid = 27835992 | pmc = 5106787 | doi = 10.1186/s12915-016-0322-x | doi-access = free }} The most intensively analyzed, and certainly the best understood pseudoenzymes in terms of cellular signalling functions are probably the pseudokinases, the pseudoproteases and the pseudophosphatases. Recently, the pseudo-deubiquitylases have also begun to gain prominence.{{cite journal | vauthors = Walden M, Masandi SK, Pawlowski K, Zeqiraj E | title = Pseudo-DUBs as allosteric activators and molecular scaffolds of protein complexes. | journal = Biochem Soc Trans | volume = 46 | issue = 2 | pages = 453–466 | date = Feb 2018 | pmid = 29472364 | doi = 10.1042/BST20160268 | s2cid = 3477709 | url = http://eprints.whiterose.ac.uk/129505/1/pseudo_dub_review_Walden_et_al_2018.pdf }}{{cite journal|vauthors=Walden M, Tian L, Ross RL, Sykora UM, Byrne DP, Hesketh EL, Masandi SK, Cassel J, George R, Ault JR, El Oualid F, Pawłowski K, Salvino JM, Eyers PA, Ranson NA, Del Galdo F, Greenberg RA, Zeqiraj E|date=May 2019|title=Metabolic control of BRISC–SHMT2 assembly regulates immune signalling|journal=Nature|volume=570|issue=7760|pages=194–199|doi=10.1038/s41586-019-1232-1|pmid=31142841|url=http://eprints.whiterose.ac.uk/147110/1/Walden_et_al_accepted_article.pdf|pmc=6914362|bibcode=2019Natur.570..194W}}
Structures and roles
The difference between enzymatically active and inactive homologues has been noted (and in some cases, understood when comparing catalytically active and inactive proteins residing in recognisable families) for some time at the sequence level,{{cite journal | vauthors = Todd AE, Orengo CA, Thornton JM | title = Sequence and structural differences between enzyme and nonenzyme homologs | journal = Structure | volume = 10 | issue = 10 | pages = 1435–51 | date = October 2002 | pmid = 12377129 | doi = 10.1016/s0969-2126(02)00861-4 | doi-access = free }} owing to the absence of key catalytic residues. Some pseudoenzymes have also been referred to as 'prozymes' when they were analysed in protozoan parasites.{{cite journal | vauthors = Willert EK, Fitzpatrick R, Phillips MA | title = Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 20 | pages = 8275–80 | date = May 2007 | pmid = 17485680 | pmc = 1895940 | doi = 10.1073/pnas.0701111104 | bibcode = 2007PNAS..104.8275W | doi-access = free }} The best studied pseudoenzymes reside amongst various key signalling superfamilies of enzymes, such as the proteases,{{cite journal | vauthors = Adrain C, Freeman M | title = New lives for old: evolution of pseudoenzyme function illustrated by iRhoms | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 8 | pages = 489–98 | date = July 2012 | pmid = 22781900 | doi = 10.1038/nrm3392 | s2cid = 806199 }} the protein kinases,{{cite journal | vauthors = Kwon A, Scott S, Taujale R, Yeung W, Kochut KJ, Eyers PA, Kannan N | title = Tracing the origin and evolution of pseudokinases across the tree of life | journal = Science Signaling | volume = 12 | issue = 578 | pages = eaav3810 | date = April 2019 | pmid = 31015289 | doi = 10.1126/scisignal.aav3810 | pmc = 6997932 }}{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–34 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | bibcode = 2002Sci...298.1912M | s2cid = 26554314 }}{{cite journal | vauthors = Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR | title = Emerging roles of pseudokinases | journal = Trends in Cell Biology | volume = 16 | issue = 9 | pages = 443–52 | date = September 2006 | pmid = 16879967 | doi = 10.1016/j.tcb.2006.07.003 }}{{cite journal | vauthors = Eyers PA, Keeshan K, Kannan N | title = Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease | journal = Trends in Cell Biology | volume = 27 | issue = 4 | pages = 284–298 | date = April 2017 | pmid = 27908682 | pmc = 5382568 | doi = 10.1016/j.tcb.2016.11.002 }}{{cite journal | vauthors = Reiterer V, Eyers PA, Farhan H | title = Day of the dead: pseudokinases and pseudophosphatases in physiology and disease | journal = Trends in Cell Biology | volume = 24 | issue = 9 | pages = 489–505 | date = September 2014 | pmid = 24818526 | doi = 10.1016/j.tcb.2014.03.008 }}{{cite journal | vauthors = Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RC, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, Alexander WS | title = The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism | journal = Immunity | volume = 39 | issue = 3 | pages = 443–53 | date = September 2013 | pmid = 24012422 | doi = 10.1016/j.immuni.2013.06.018 | doi-access = free }}{{cite journal | vauthors = Wishart MJ, Dixon JE | title = Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains | journal = Trends in Biochemical Sciences | volume = 23 | issue = 8 | pages = 301–6 | date = August 1998 | pmid = 9757831 | doi = 10.1016/s0968-0004(98)01241-9 }} protein phosphatases{{cite journal | vauthors = Reiterer V, Eyers PA, Farhan H | title = Day of the dead: pseudokinases and pseudophosphatases in physiology and disease | journal = Trends in Cell Biology | volume = 24 | issue = 9 | pages = 489–505 | date = September 2014 | pmid = 24818526 | doi = 10.1016/j.tcb.2014.03.008 }}{{cite journal | vauthors = Chen MJ, Dixon JE, Manning G | title = Genomics and evolution of protein phosphatases | journal = Science Signaling | volume = 10 | issue = 474 | pages = eaag1796 | date = April 2017 | pmid = 28400531 | doi = 10.1126/scisignal.aag1796 | s2cid = 41041971 }} and ubiquitin modifying enzymes.{{cite journal | vauthors = Zeqiraj E, Tian L, Piggott CA, Pillon MC, Duffy NM, Ceccarelli DF, Keszei AF, Lorenzen K, Kurinov I, Orlicky S, Gish GD, Heck AJ, Guarné A, Greenberg RA, Sicheri F | title = Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function | journal = Molecular Cell | volume = 59 | issue = 6 | pages = 970–83 | date = September 2015 | pmid = 26344097 | pmc = 4579573 | doi = 10.1016/j.molcel.2015.07.028 }}{{cite journal | vauthors = Strickson S, Emmerich CH, Goh ET, Zhang J, Kelsall IR, Macartney T, Hastie CJ, Knebel A, Peggie M, Marchesi F, Arthur JS, Cohen P | title = Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 17 | pages = E3481–E3489 | date = April 2017 | pmid = 28404732 | pmc = 5410814 | doi = 10.1073/pnas.1702367114 | bibcode = 2017PNAS..114E3481S | doi-access = free }} The role of pseudoenzymes as "pseudo scaffolds" has also been recognised {{cite journal | vauthors = Aggarwal-Howarth S, Scott JD | title = Pseudoscaffolds and anchoring proteins: the difference is in the details | journal = Biochemical Society Transactions | volume = 45 | issue = 2 | pages = 371–379 | date = April 2017 | pmid = 28408477 | pmc = 5497583 | doi = 10.1042/bst20160329 }} and pseudoenzymes are now beginning to be more thoroughly studied in terms of their biology and function, in large part because they are also interesting potential targets (or anti-targets) for drug design in the context of intracellular cellular signalling complexes.{{cite journal | vauthors = Foulkes DM, Byrne DP, Bailey FP, Eyers PA | title = Tribbles pseudokinases: novel targets for chemical biology and drug discovery? | journal = Biochemical Society Transactions | volume = 43 | issue = 5 | pages = 1095–103 | date = October 2015 | pmid = 26517930 | doi = 10.1042/bst20150109 }}{{cite journal | vauthors = Byrne DP, Foulkes DM, Eyers PA | title = Pseudokinases: update on their functions and evaluation as new drug targets | journal = Future Medicinal Chemistry | volume = 9 | issue = 2 | pages = 245–265 | date = January 2017 | pmid = 28097887 | doi = 10.4155/fmc-2016-0207 | doi-access = free }}
Examples classes
| class="wikitable" | ||
| Class | Function | Examples {{cite journal | vauthors = Murphy JM, Farhan H, Eyers PA | title = Bio-Zombie: the rise of pseudoenzymes in biology | journal = Biochemical Society Transactions | volume = 45 | issue = 2 | pages = 537–544 | date = April 2017 | pmid = 28408493 | doi = 10.1042/bst20160400 }} |
|---|---|---|
| rowspan="2" | Pseudokinase | Allosteric regulation of conventional protein kinase | STRADα regulates activity of the conventional protein kinase, LKB1
JAK1-3 and TYK2 C-terminal tyrosine kinase domains are regulated by their adjacent pseudokinase domain KSR1/2 regulates activation of the conventional protein kinase, Raf |
| Allosteric regulation of other enzymes | VRK3 regulates activity of the phosphatase, VHR | |
| Protein interaction domain | MLKL pseudokinase regulates exposure of the executioner four-helix bundle domain, and engagement of HSP90:Cdc37 | |
| Scaffold for assembly of signalling complexes | Tribbles proteins nucleate assembly of a complex between a substrate (C/EBPα) and the E3 Ubiquitin ligase, COP1 | |
| Pseudo-Histidine kinase | Protein interaction domain | Caulobacter DivL binds the phosphorylated response regulator, DivK, allowing DivL to negatively regulate the asymmetric cell division regulatory kinase, CckA |
| rowspan="4" | Pseudophosphatase | Occlusion of conventional phosphatase access to substrate | EGG-4/EGG-5 binds to the phosphorylated activation loop of the kinase, MBK-2
STYX competes with DUSP4 for binding to ERK1/2 |
| Allosteric regulation of conventional phosphatases | MTMR13 binds and promotes lipid phosphatase activity of MTMR2 | |
| Regulation of protein localisation in a cell | STYX acts as a nuclear anchor for ERK1/2 | |
| Regulation of signalling complex assembly | STYX binds the F-box protein, FBXW7, to inhibit its recruitment to the SCF Ubiquitin ligase complex | |
| rowspan="2" | Pseudoprotease | Allosteric regulator of conventional protease | cFLIP binds and inhibits the cysteine protease, Caspase-8, to block extrinsic apoptosis |
| Regulation of protein localisation in a cell | Mammalian iRhom proteins bind and regulate trafficking single pass transmembrane proteins to plasma membrane or ER-associated degradation pathway | |
| Pseudodeubiquitinase (pseudoDUB) | Allosteric regulator of conventional DUB | KIAA0157 is crucial to assembly of a higher order heterotetramer with DUB, BRCC36, and DUB activity |
| rowspan="2" | Pseudoligase (pseudo-Ubiquitin E2) | Allosteric regulator of conventional E2 ligase | Mms2 is a ubiquitin E2 variant (UEV) that binds active E2, Ubc13, to direct K63 ubiquitin linkages |
| Regulation of protein localisation in a cell | Tsg101 is a component of the ESCRT-I trafficking complex, and plays a key role in HIV-1 Gag binding and HIV budding | |
| Pseudoligase (pseudo-Ubiquitin E3) | Possible allosteric regulator of conventional RBR family E3 ligase | BRcat regulates interdomain architecture in RBR family E3 Ubiquitin ligases, such as Parkin and Ariadne-1/2 |
| Pseudonuclease | Allosteric regulator of conventional nuclease | CPSF-100 is a component of the pre-mRNA 3´ end processing complex containing the active counterpart, CPSF-73 |
| PseudoATPase | Allosteric regulator of conventional ATPase | EccC comprises two pseudoATPase domains that regulate the N-terminal conventional ATPase domain |
| rowspan="3" | PseudoGTPase | Allosteric regulator of conventional GTPase | GTP-bound Rnd1 or Rnd3/RhoE bind p190RhoGAP to regulate the catalytic activity of the conventional GTPase, RhoA |
| Scaffold for assembly of signalling complexes | MiD51, which is catalytically dead but binds GDP or ADP, is part of a complex that recruits Drp1 to mediate mitochondrial fission. CENP-M cannot bind GTP or switch conformations, but is essential for nucleating the CENP-I, CENP-H, CENP-K small GTPase complex to regulate kinetochore assembly | |
| Regulation of protein localisation in a cell | Yeast light intermediate domain (LIC) is a pseudoGTPase, devoid of nucleotide binding, which binds the dynein motor to cargo. Human LIC binds GDP in preference to GTP, suggesting nucleotide binding could confer stability rather than underlying a switch mechanism. | |
| Pseudochitinase | Substrate recruitment or sequestration | YKL-39 binds, but does not process, chitooligosaccharides via 5 binding subsites |
| Pseudosialidase | Scaffold for assembly of signalling complexes | CyRPA nucleates assembly of the P. falciparum PfRh5/PfRipr complex that binds the erythrocyte receptor, basigin, and mediates host cell invasion |
| Pseudolyase | Allosteric activation of conventional enzyme counterpart | Prozyme heterodimerisation with S-adenosylmethionine decarboxylase (AdoMetDC) activates catalytic activity 1000-fold |
| Pseudotransferase | Allosteric activation of cellular enzyme counterpart | Viral GAT recruits cellular PFAS to deaminate RIG-I and counter host antiviral defence. T. brucei deoxyhypusine synthase (TbDHS) dead paralog, DHSp, binds to and activates DHSc >1000-fold. |
| Pseudo-histone acetyl transferase (pseudoHAT) | Possible scaffold for assembly of signalling complexes | Human O-GlcNAcase (OGA) lacks catalytic residues and acetyl CoA binding, unlike bacterial counterpart |
| rowspan="2" | Pseudo-phospholipase | Possible scaffold for assembly of signalling complexes | FAM83 family proteins presumed to have acquired new functions in preference to ancestral phospholipase D catalytic activity |
| Allosteric inactivation of conventional enzyme counterpart | Viper phospholipase A2 inhibitor structurally resembles the human cellular protein it targets, phospholipase A2. | |
| Pseudo-oxidoreductase | Allosteric inactivation of conventional enzyme counterpart | ALDH2*2 thwarts assembly of the active counterpart, ALDH2*1, into a tetramer. |
| Pseudo-dismutase | Allosteric activation of conventional enzyme counterpart | Copper chaperone for superoxide dismutase (CCS) binds and activates catalysis by its enzyme counterpart, SOD1 |
| Pseudo-dihydroorotase | Regulating folding or complex assembly of conventional enzyme | Pseudomonas pDHO is required for either folding of the aspartate transcarbamoylase catalytic subunit, or its assembly into an active oligomer |
| Pseudo-RNase | Facilitating complex assembly/stability and promoting association of catalytic paralog | KREPB4 may act as a pseudoenzyme to form the noncatalytic half of an RNase III heterodimer with the editing endonuclease(s){{cite journal | vauthors = McDermott SM, Stuart K | title = The essential functions of KREPB4 are developmentally distinct and required for endonuclease association with editosomes | journal = RNA | volume = 23 | issue = 11 | pages = 1672–1684 | date = November 2017 | pmid = 28802260 | pmc = 5648035 | doi = 10.1261/rna.062786.117 }} |
See also
References
{{Reflist}}
External links
- {{cite web|url=https://www.liverpool.ac.uk/integrative-biology/staff/patrick-eyers/ |title=Patrick Eyers - University of Liverpool |website=Liverpool.ac.uk |date= |access-date=2017-01-16}}