TPP riboswitch
| TPP riboswitch (THI element) | |
|---|---|
 Predicted secondary structure and sequence conservation of TPP | |
| Identifiers | |
| Symbol | TPP |
| Alt. Symbols | THI |
| Rfam | RF00059 |
| Other data | |
| RNA type | Cis-reg; riboswitch |
| Domain(s) | Eukaryota; Bacteria; Archaea |
| GO | GO:0030976 |
| SO | SO:0000035 |
| PDB structures | PDBe 4nyc |
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[1][2] 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 B1), an essential coenzyme used by all kinds of life.[3][4][5]
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.[6] The x-ray crystal structure of the TPP riboswitch aptamer has been solved.[7]
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.[9][4] Six groups of TPP riboswitches are known in fungi, the first two of perform this function.[10]
Analysis of operon structures has identified a large number of new candidate thiamin-regulated genes, mostly transporters, in various bacteria.[11] The four remaining groups of fungal TPP riboswitches control transporters.[10]
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.[9] PT is not used clinically as an antibiotic. In addition, the ESKAPE pathogens carry resistant riboswitches.[12] (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.)[13]
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.[13]
See also
References
- ↑ Winkler W, Nahvi A, Breaker RR (October 2002). "Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression". Nature. 419 (6910): 952–956. Bibcode:2002Natur.419..952W. doi:10.1038/nature01145. PMID 12410317. S2CID 4408592.
- ↑ Mironov AS, Gusarov I, Rafikov R, Lopez LE, Shatalin K, Kreneva RA, Perumov DA, Nudler E (November 2002). "Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria". Cell. 111 (5): 747–756. doi:10.1016/S0092-8674(02)01134-0. PMID 12464185.
- ↑ Sudarsan N, Barrick JE, Breaker RR (June 2003). "Metabolite-binding RNA domains are present in the genes of eukaryotes". RNA. 9 (6): 644–647. doi:10.1261/rna.5090103. PMC 1370431. PMID 12756322.
- 1 2 Bocobza S, Adato A, Mandel T, Shapira M, Nudler E, Aharoni A (November 2007). "Riboswitch-dependent gene regulation and its evolution in the plant kingdom". Genes & Development. 21 (22): 2874–2879. doi:10.1101/gad.443907. PMC 2049190. PMID 18006684.
- ↑ Kubodera T, Watanabe M, Yoshiuchi K, Yamashita N, Nishimura A, Nakai S, Gomi K, Hanamoto H (December 2003). "Thiamine-regulated gene expression of Aspergillus oryzae thiA requires splicing of the intron containing a riboswitch-like domain in the 5'-UTR". FEBS Letters. 555 (3): 516–520. Bibcode:2003FEBSL.555..516K. doi:10.1016/S0014-5793(03)01335-8. PMID 14675766.
- ↑ Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS (December 2002). "Comparative genomics of thiamin biosynthesis in procaryotes. New genes and regulatory mechanisms". The Journal of Biological Chemistry. 277 (50): 48949–48959. doi:10.1074/jbc.M208965200. PMID 12376536.
- ↑ Serganov A, Polonskaia A, Phan AT, Breaker RR, Patel DJ (June 2006). "Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch". Nature. 441 (7097): 1167–1171. Bibcode:2006Natur.441.1167S. doi:10.1038/nature04740. PMC 4689313. PMID 16728979.
- ↑ Edwards TE, Ferré-D'Amaré AR (September 2006). "Crystal structures of the thi-box riboswitch bound to thiamine pyrophosphate analogs reveal adaptive RNA-small molecule recognition". Structure. 14 (9): 1459–1468. doi:10.1016/j.str.2006.07.008. PMID 16962976.
- 1 2 Sudarsan, Narasimhan; Cohen-Chalamish, Smadar; Nakamura, Shingo; Emilsson, Gail Mitchell; Breaker, Ronald R. (December 2005). "Thiamine Pyrophosphate Riboswitches Are Targets for the Antimicrobial Compound Pyrithiamine". Chemistry & Biology. 12 (12): 1325–1335. doi:10.1016/j.chembiol.2005.10.007. PMID 16356850.
- 1 2 Vargas-Junior, Valdemir; Guimarães, Ana Carolina Ramos; Caffarena, Ernesto Raul; Antunes, Deborah (24 December 2024). "Genome-Wide Exploration of Thiamin Pyrophosphate Riboswitches in Medically Relevant Fungi Reveals Diverse Distribution and Implications for Antimicrobial Drug Targeting". ACS Omega. 9 (51): 50134–50146. doi:10.1021/acsomega.4c00158. PMC 11683625. PMID 39741832.
- ↑ Miranda-Ríos J, Navarro M, Soberón M (August 2001). "A conserved RNA structure (thi box) is involved in regulation of thiamin biosynthetic gene expression in bacteria". Proceedings of the National Academy of Sciences of the United States of America. 98 (17): 9736–9741. doi:10.1073/pnas.161168098. PMC 55522. PMID 11470904.
- ↑ Hübenthal, A; Panchal, V; Brenk, R; Mack, M (20 November 2025). "Functional analysis of thiamine pyrophosphate-responsive riboswitches in human bacterial pathogens of the ESKAPE group using a dual-luciferase reporter gene assay". Journal of Bacteriology. 207 (11): e0030825. doi:10.1128/jb.00308-25. PMC 12632268. PMID 41065437.
- 1 2 Lünse, CE; Scott, FJ; Suckling, CJ; Mayer, G (2014). "Novel TPP-riboswitch activators bypass metabolic enzyme dependency". Frontiers in Chemistry. 2: 53. Bibcode:2014FrCh....2...53M. doi:10.3389/fchem.2014.00053. PMC 4112796. PMID 25121086.