Rhodoquinone

Last updated
Rhodoquinone
Rhodoquinone.svg
Names
IUPAC name
5-[(2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-Decamethyltetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl]-2-amino-3-methoxy-6-methylcyclohexa-2,5-diene-1,4-dione
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • InChI=1S/C58H89NO3/c1-43(2)23-14-24-44(3)25-15-26-45(4)27-16-28-46(5)29-17-30-47(6)31-18-32-48(7)33-19-34-49(8)35-20-36-50(9)37-21-38-51(10)39-22-40-52(11)41-42-54-53(12)56(60)55(59)58(62-13)57(54)61/h23,25,27,29,31,33,35,37,39,41H,14-22,24,26,28,30,32,34,36,38,40,42,59H2,1-13H3/b44-25+,45-27+,46-29+,47-31+,48-33+,49-35+,50-37+,51-39+,52-41+
    Key: WDVDSFZLRFLVJT-AVRCVIBKSA-N
  • CC1=C(C(=O)C(=C(C1=O)N)OC)C/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CC/C=C(\C)/CCC=C(C)C
Properties
C58H89NO3
Molar mass 848.354 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Rhodoquinone (RQ) is a modified ubiquinone-like molecule that is an important cofactor used in anaerobic energy metabolism by many organisms. Recently, it has gained attention as a potential anthelmintic drug target due to the fact that parasitic hosts do not synthesize or use this cofactor. Because this cofactor is used in low oxygen environments, many helminth-like organisms have adapted to survive host environments such as the areas within the gastrointestinal tracks. [1] [2]

Contents

Biosynthesis

Currently the biosynthesis of rhodoquinone (RQ) is still being debated, but there are two main biosynthetic pathways that are being researched. The first pathway requires the organism to produce ubiquinone (UQ) before the amino group can be added onto the quinone ring. The second pathway allows RQ to be synthesized without any UQ being present by using tryptophan metabolites instead. [3]

Figure 1. Proposed biosynthesis of rhodoquinone Rhodoquinone-biosynthesis-1a.png
Figure 1. Proposed biosynthesis of rhodoquinone

In the case of the prokaryotic organism R. rubrum, RQ has been shown to be synthesized by addition of an amino group to a pre-existing UQ; thus UQ needs to be present as a precursor before RQ can be made. Figure 1 shows the biosynthesis of UQ in yeast and E. coli where 'n' represents the number of isoprene units between various organisms. Dimethylallyl diphosphate A and isopentyl diphosphate B come together to form polyisoprenyl diphosphate C. With the addition of p-hydroxybenzoic acid, the product that arises is 3-polyprenyl-4-hydroxybenzoic acid D. The next three steps of synthesis varies between different organisms, but molecule E is made across all organisms and through oxidation, demethyldemethoxyubiquinone (DDMQ) is eventually formed. RQ has been theorized to be synthesized from DDMQn, DMQn, DMeQn, or UQn, as shown with the dashed arrows. Recent studies have shown that Path 4 - RQ biosynthesis via UQ, is the favored route. [4] It has been further shown that the gene rquA is required for the biosynthesis of RQ in R. rubrum, and that RquA catalyzes the conversion of UQ to RQ. [5] [6] The RquA protein uses S-adenosyl-L-methionine as the amino donor to convert UQ to RQ in an unusual Mn(II)-catalyzed reaction. [7]

Figure 2. Alternative proposed biosynthesis for rhodoquinone Rhodoquinone-biosynthesis-1b.png
Figure 2. Alternative proposed biosynthesis for rhodoquinone

Research in C. elegans has shown an alternative path for production of RQ. Even after knocking out all UQ production, RQ is still present within those mutant strains. Based on this data, RQ production is not solely based on UQ-like molecules and instead can be made via tryptophan metabolites. Therefore, the amino group that is added in late stages of RQ biosynthesis in rquA-containing species is instead present throughout intermediate stages of RQ biosynthesis in C. elegans. With this proposed biosynthesis, the kynurenine pathway still needs to be upregulated, and activity from certain genes like kynu-1 which encodes for the KYNU-1 enzyme that catalyzes production of 3-hydroxy-L-kynurenine to 3-hydroxyanthranilic acid, needs to be upheld. [8] [9] Recent work has revealed that alternative splicing of the coq-2 polyprenyltransferase gene controls the level of RQ in animals. [10] Animals that produce RQ (e.g. C. elegans and helminth parasites) contain both COQ-2 protein isoforms (COQ-2a and COQ-2e), and COQ-2e catalyzes prenylation of 3-hydroxyanthranilic acid (instead of p-hydroxybenzoic acid) which leads to RQ.

Rhodoquinone in Eukaryotes

The COQ-2e isoform and RQ have been detected in Mullosca [11] , Platyhelminthes [12] and Nematoda [13] . The presence of RquA and RQ has been confirmed in only a few single celled eukaryotes, namely Pygsuia biforma [14] and Euglena gracilis [15] , although the RquA gene has been identified in a wide array of eukaryotic genome and transcriptomes [14] .

References

  1. ↑ "[Prevention and control of schistosomiasis and soil-transmitted helminthiasis:report of a WHO expert committee]". World Health Organization. 49 (3): 57. June 2012. ISBN   978-92-4-120912-0.
  2. ↑ Stairs CW, Eme L, Muñoz-Gómez SA, Cohen A, Dellaire G, Shepherd JN, et al. (April 2018). "Microbial eukaryotes have adapted to hypoxia by horizontal acquisitions of a gene involved in rhodoquinone biosynthesis". eLife. 7 e34292. doi: 10.7554/eLife.34292 . PMC   5953543 . PMID   29697049.
  3. ↑ Salinas G, Langelaan DN, Shepherd JN (November 2020). "Rhodoquinone in bacteria and animals: Two distinct pathways for biosynthesis of this key electron transporter used in anaerobic bioenergetics". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1861 (11) 148278. doi: 10.1016/j.bbabio.2020.148278 . PMID   32735860.
  4. ↑ Brajcich BC, Iarocci AL, Johnstone LA, Morgan RK, Lonjers ZT, Hotchko MJ, et al. (January 2010). "Evidence that ubiquinone is a required intermediate for rhodoquinone biosynthesis in Rhodospirillum rubrum". Journal of Bacteriology. 192 (2): 436–445. doi: 10.1128/JB.01040-09 . PMC   2805321 . PMID   19933361.
  5. ↑ Lonjers ZT, Dickson EL, Chu TP, Kreutz JE, Neacsu FA, Anders KR, Shepherd JN (March 2012). "Identification of a new gene required for the biosynthesis of rhodoquinone in Rhodospirillum rubrum". Journal of Bacteriology. 194 (5): 965–971. doi: 10.1128/JB.06319-11 . PMC   3294814 . PMID   22194448.
  6. ↑ Bernert AC, Jacobs EJ, Reinl SR, Choi CC, Roberts Buceta PM, Culver JC, et al. (September 2019). "Recombinant RquA catalyzes the in vivo conversion of ubiquinone to rhodoquinone in Escherichia coli and Saccharomyces cerevisiae". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1864 (9): 1226–1234. doi:10.1016/j.bbalip.2019.05.007. PMC   6874216 . PMID   31121262.
  7. ↑ Neupane T, Chambers LR, Godfrey AJ, Monlux MM, Jacobs EJ, Whitworth S, et al. (August 2022). "Microbial rhodoquinone biosynthesis proceeds via an atypical RquA-catalyzed amino transfer from S-adenosyl-L-methionine to ubiquinone". Communications Chemistry. 5 (1) 89. Bibcode:2022CmChe...5...89N. doi: 10.1038/s42004-022-00711-6 . PMC   9814641 . PMID   36697674.
  8. ↑ Roberts Buceta PM, Romanelli-Cedrez L, Babcock SJ, Xun H, VonPaige ML, Higley TW, et al. (July 2019). "The kynurenine pathway is essential for rhodoquinone biosynthesis in Caenorhabditis elegans". The Journal of Biological Chemistry. 294 (28): 11047–11053. doi: 10.1074/jbc.AC119.009475 . PMC   6635453 . PMID   31177094.
  9. ↑ Del Borrello S, Lautens M, Dolan K, Tan JH, Davie T, Schertzberg MR, et al. (June 2019). "Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway". eLife. 8 e48165. doi: 10.7554/eLife.48165 . PMC   6656428 . PMID   31232688.
  10. ↑ Tan JH, Lautens M, Romanelli-Cedrez L, Wang J, Schertzberg MR, Reinl SR, et al. (August 2020). "Alternative splicing of coq-2 controls the levels of rhodoquinone in animals". eLife. 9 e56376. doi: 10.7554/eLife.56376 . PMC   7434440 . PMID   32744503.
  11. ↑ Hellemond, Jaap J. Van; Klockiewicz, Maciej; Gaasenbeek, Cor P. H.; Roos, Marleen H.; Tielens, Aloysius G. M. (1995-12-29). "Rhodoquinone and Complex II of the Electron Transport Chain in Anaerobically Functioning Eukaryotes (∗)". Journal of Biological Chemistry. 270 (52): 31065–31070. doi: 10.1074/jbc.270.52.31065 . ISSN   0021-9258. PMID   8537365.
  12. ↑ Fioravanti, Carmen F.; Kim, Younghee (1988-03-01). "Rhodoquinone requirement of the Hymenolepis diminuta mitochondrial electron transport system". Molecular and Biochemical Parasitology. 28 (2): 129–134. doi:10.1016/0166-6851(88)90060-6. ISSN   0166-6851. PMID   3367932.
  13. ↑ Allen, Patricia C. (October 1973). "Helminths: Comparison of their rhodoquinone". Experimental Parasitology. 34 (2): 211–219. doi:10.1016/0014-4894(73)90080-5. ISSN   0014-4894. PMID   4795616.
  14. 1 2 Stairs, Courtney W; Eme, Laura; Muñoz-Gómez, Sergio A; Cohen, Alejandro; Dellaire, Graham; Shepherd, Jennifer N; Fawcett, James P; Roger, Andrew J (2018-04-26). "Microbial eukaryotes have adapted to hypoxia by horizontal acquisitions of a gene involved in rhodoquinone biosynthesis". eLife. 7 e34292. doi: 10.7554/eLife.34292 . ISSN   2050-084X. PMC   5953543 . PMID   29697049.
  15. ↑ Threlfall, D. R. (1972-11-30). "Incorporation of l-[Me-2H3]methionine into isoprenoid quinones and related compounds by Euglena gracilis". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 280 (3): 472–480. doi:10.1016/0005-2760(72)90255-X. ISSN   0005-2760. PMID   4629978.
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