{{Short description|RNA secondary structure}} {{Infobox rfam | Name = TPP riboswitch (THI element) | image = RF00059-rscape.svg | width = | caption = Predicted secondary structure and sequence conservation of TPP | Symbol = TPP | AltSymbols = THI | Rfam = RF00059 | miRBase = | miRBase_family = | RNA_type = Cis-reg; riboswitch | Tax_domain = Eukaryota; Bacteria; Archaea | GO = {{GO|0030976}} | SO = {{SO|0000035}} | CAS_number = | EntrezGene = | HGNCid = | OMIM = | PDB = 4nyc | RefSeq = | Chromosome = | Arm = | Band = | LocusSupplementaryData = }}
The '''TPP riboswitch''', also known as the '''THI element''' and '''Thi-box riboswitch''', is a highly conserved RNA secondary structure. It serves as a riboswitch<ref name=Winkler>{{cite journal | vauthors = Winkler W, Nahvi A, Breaker RR | title = Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression | journal = Nature | volume = 419 | issue = 6910 | pages = 952–956 | date = October 2002 | pmid = 12410317 | doi = 10.1038/nature01145 | bibcode = 2002Natur.419..952W | s2cid = 4408592 }}</ref><ref>{{cite journal | vauthors = Mironov AS, Gusarov I, Rafikov R, Lopez LE, Shatalin K, Kreneva RA, Perumov DA, Nudler E | title = Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria | journal = Cell | volume = 111 | issue = 5 | pages = 747–756 | date = November 2002 | pmid = 12464185 | doi = 10.1016/S0092-8674(02)01134-0 | doi-access = free }}</ref> that binds thiamine pyrophosphate (TPP) directly and modulates gene expression through a variety of mechanisms in archaea, bacteria and eukaryotes. TPP is the active form of thiamine (vitamin B<sub>1</sub>), an essential coenzyme used by all kinds of life.<ref>{{cite journal | vauthors = Sudarsan N, Barrick JE, Breaker RR | title = Metabolite-binding RNA domains are present in the genes of eukaryotes | journal = RNA | volume = 9 | issue = 6 | pages = 644–647 | date = June 2003 | pmid = 12756322 | pmc = 1370431 | doi = 10.1261/rna.5090103 }}</ref><ref name=Bocobza>{{cite journal | vauthors = Bocobza S, Adato A, Mandel T, Shapira M, Nudler E, Aharoni A | title = Riboswitch-dependent gene regulation and its evolution in the plant kingdom | journal = Genes & Development | volume = 21 | issue = 22 | pages = 2874–2879 | date = November 2007 | pmid = 18006684 | pmc = 2049190 | doi = 10.1101/gad.443907 }}</ref><ref>{{cite journal | vauthors = Kubodera T, Watanabe M, Yoshiuchi K, Yamashita N, Nishimura A, Nakai S, Gomi K, Hanamoto H | title = Thiamine-regulated gene expression of Aspergillus oryzae thiA requires splicing of the intron containing a riboswitch-like domain in the 5'-UTR | journal = FEBS Letters | volume = 555 | issue = 3 | pages = 516–520 | date = December 2003 | pmid = 14675766 | doi = 10.1016/S0014-5793(03)01335-8 | doi-access = free | bibcode = 2003FEBSL.555..516K }}</ref>
The THI element is an extension of a previously detected thiamin-regulatory element, the thi box, there is considerable variability in the predicted length and structures of the additional and facultative stem-loops represented in dark blue in the secondary structure diagram.<ref>{{cite journal | vauthors = Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS | title = Comparative genomics of thiamin biosynthesis in procaryotes. New genes and regulatory mechanisms | journal = The Journal of Biological Chemistry | volume = 277 | issue = 50 | pages = 48949–48959 | date = December 2002 | pmid = 12376536 | doi = 10.1074/jbc.M208965200 | doi-access = free }}</ref> The x-ray crystal structure of the TPP riboswitch aptamer has been solved.<ref>{{cite journal | vauthors = Serganov A, Polonskaia A, Phan AT, Breaker RR, Patel DJ | title = Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch | journal = Nature | volume = 441 | issue = 7097 | pages = 1167–1171 | date = June 2006 | pmid = 16728979 | pmc = 4689313 | doi = 10.1038/nature04740 | bibcode = 2006Natur.441.1167S }}</ref>
<gallery> File:TPP_riboswitch_pdb-2hoj.png | Experimental 3D structure of the TPP riboswitch ({{PDB|2HOJ}}).<ref name="pmid16962976">{{cite journal | vauthors = Edwards TE, Ferré-D'Amaré AR | title = Crystal structures of the thi-box riboswitch bound to thiamine pyrophosphate analogs reveal adaptive RNA-small molecule recognition | journal = Structure | volume = 14 | issue = 9 | pages = 1459–1468 | date = September 2006 | pmid = 16962976 | doi = 10.1016/j.str.2006.07.008 }}</ref> </gallery>
== Targets and mechanisms == The classical function of the TPP riboswitch is to control thiamine biosynthetic genes so that they are only translated when needed. This function is usually accompanied by the classical positioning of the riboswitch in the 5' UTR; when bound to TPP, the riboswitch causes aberrant splicing, making the mRNA fail to translate.<ref name=Sudarsan>{{cite journal |last1=Sudarsan |first1=Narasimhan |last2=Cohen-Chalamish |first2=Smadar |last3=Nakamura |first3=Shingo |last4=Emilsson |first4=Gail Mitchell |last5=Breaker |first5=Ronald R. |title=Thiamine Pyrophosphate Riboswitches Are Targets for the Antimicrobial Compound Pyrithiamine |journal=Chemistry & Biology |date=December 2005 |volume=12 |issue=12 |pages=1325–1335 |doi=10.1016/j.chembiol.2005.10.007 |pmid=16356850 }}</ref><ref name=Bocobza/> Six groups of TPP riboswitches are known in fungi, the first two of perform this function.<ref name="Vargas-Junior24">{{cite journal |last1=Vargas-Junior |first1=Valdemir |last2=Guimarães |first2=Ana Carolina Ramos |last3=Caffarena |first3=Ernesto Raul |last4=Antunes |first4=Deborah |title=Genome-Wide Exploration of Thiamin Pyrophosphate Riboswitches in Medically Relevant Fungi Reveals Diverse Distribution and Implications for Antimicrobial Drug Targeting |journal=ACS Omega |date=24 December 2024 |volume=9 |issue=51 |pages=50134–50146 |doi=10.1021/acsomega.4c00158 |doi-access=free |pmid=39741832 |pmc=11683625 }}</ref>
Analysis of operon structures has identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various bacteria.<ref>{{cite journal | vauthors = Miranda-Ríos J, Navarro M, Soberón M | title = A conserved RNA structure (thi box) is involved in regulation of thiamin biosynthetic gene expression in bacteria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 17 | pages = 9736–9741 | date = August 2001 | pmid = 11470904 | pmc = 55522 | doi = 10.1073/pnas.161168098 | doi-access = free }}</ref> The four remaining groups of fungal TPP riboswitches control transporters.<ref name="Vargas-Junior24"/>
== Ligands == Pyrithiamine (PT) is often used in the laboratory as a thiamine antagonist because it inhibits thiamine-related enzymes. PT pyrophosphate also binds to the TPP riboswitch and downregulates the target genes, making the inhibition harder to escape from. However, riboswitch resistance often occurs by mutations that abolish PT binding.<ref name=Sudarsan/> PT is not used clinically as an antibiotic. In addition, the ESKAPE pathogens carry resistant riboswitches.<ref>{{cite journal |last1=Hübenthal |first1=A |last2=Panchal |first2=V |last3=Brenk |first3=R |last4=Mack |first4=M |title=Functional analysis of thiamine pyrophosphate-responsive riboswitches in human bacterial pathogens of the ESKAPE group using a dual-luciferase reporter gene assay. |journal=Journal of Bacteriology |date=20 November 2025 |volume=207 |issue=11 |pages=e0030825 |doi=10.1128/jb.00308-25 |pmid=41065437 |pmc=12632268 }}</ref> (It is also possible that PT can directly bind the riboswitch, as it does not require thiamine kinase to work in ''E. coli'' like thiamine itself or other analogues.)<ref name=Lünse14/>
Nevertheless, there remains some hope in exploiting the TPP riboswitch as a way to disrupt the metabolism of pathogens: after all, it is not found in humans but found in most (if not all) of the pathogenic bacteria and fungi.<ref name=Lünse14>{{cite journal |last1=Lünse |first1=CE |last2=Scott |first2=FJ |last3=Suckling |first3=CJ |last4=Mayer |first4=G |title=Novel TPP-riboswitch activators bypass metabolic enzyme dependency. |journal=Frontiers in Chemistry |date=2014 |volume=2 |pages=53 |doi=10.3389/fchem.2014.00053 |doi-access=free |pmid=25121086 |pmc=4112796 |bibcode=2014FrCh....2...53M }}</ref>
== See also ==
* Tetrahydrofolate riboswitch * FMN riboswitch
== References == {{reflist}}
== External links == * {{Rfam|id=RF00059|name=TPP riboswitch (THI element)}} * [http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2HOJ PDB entry for the TPP riboswitch tertiary structure]
Category:Cis-regulatory RNA elements Category:Riboswitch {{molecular-cell-biology-stub}}