Rhodotorulic Acid and its Derivatives: Synthesis, Properties, and Applications
  • * (Excluding Mailing and Handling)

Abstract

Siderophores are low molecular weight compounds produced by microorganisms to scavenge iron in iron-deficient environments. Rhodotorulic acid, a natural hydroxamate siderophore, plays a vital role in iron acquisition for fungi and bacteria. As the simplest natural hydroxamate siderophore, it exhibits a high affinity for ferric ions, enabling it to form stable complexes that facilitate iron uptake and transport within microorganisms. This article provides a comprehensive analysis of this hydroxamate siderophore, rhodotorulic acid, its synthesis, physicochemical properties, and biological significance. It also explores its applications in antifungal and plant protection strategies. Insights into RA derivatives reveal distinct biological effects and applications with potential in various fields, from antioxidants to antifungals. Rhodotorulic acid and its derivatives show promise for novel therapies, plant protection strategies, and iron supplementation in agriculture. Understanding their properties could advance science and medicine with sustainable practices.

[1]
Hider, R.C.; Kong, X. Chemistry and biology of siderophores. Nat. Prod. Rep., 2010, 27(5), 637-657.
[http://dx.doi.org/10.1039/b906679a] [PMID: 20376388]
[2]
Miethke, M.; Marahiel, M.A. Siderophore-based iron acquisition and pathogen control. Microbiol. Mol. Biol. Rev., 2007, 71(3), 413-451.
[http://dx.doi.org/10.1128/MMBR.00012-07]
[3]
Haas, H. Molecular genetics of fungal siderophore biosynthesis and uptake: The role of siderophores in iron uptake and storage. Appl. Microbiol. Biotechnol., 2003, 62(4), 316-330.
[http://dx.doi.org/10.1007/s00253-003-1335-2] [PMID: 12759789]
[4]
Raymond, K.N.; Allred, B.E.; Sia, A.K. Coordination chemistry of microbial iron transport. Acc. Chem. Res., 2015, 48(9), 2496-2505.
[http://dx.doi.org/10.1021/acs.accounts.5b00301] [PMID: 26332443]
[5]
Messenger, A.J.M.; Barclay, R. Bacteria, iron and pathogenicity. Biochem. Educ., 1983, 11(2), 54-63.
[http://dx.doi.org/10.1016/0307-4412(83)90043-2]
[6]
Sah, S.; Singh, R. Siderophore: Structural and functional characterisation – a comprehensive review. Agriculture, 2015, 61, 97-114.
[7]
Lawlor, M.S.; O’Connor, C.; Miller, V.L. Yersiniabactin is a virulence factor for Klebsiella pneumoniae during pulmonary infection. Infect. Immun., 2007, 75(3), 1463-1472.
[http://dx.doi.org/10.1128/IAI.00372-06] [PMID: 17220312]
[8]
Haas, H. Fungal siderophore metabolism with a focus on Aspergillus fumigatus. Nat. Prod. Rep., 2014, 31(10), 1266-1276.
[http://dx.doi.org/10.1039/C4NP00071D] [PMID: 25140791]
[9]
Grinter, R.; Lithgow, T. Determination of the molecular basis for coprogen import by Gram-negative bacteria. Intercollegiate US-China J., 2019, 6(3), 401-411.
[http://dx.doi.org/10.1107/S2052252519002926]
[10]
Tilbrook, G.S.; Hider, R.C. Iron chelators for clinical use. Met. Ions Biol. Syst., 1998, 35, 691-730.
[PMID: 9444773]
[11]
Stradling, G.N. Decorporation of actinides: a review of recent research. J. Alloys Compd., 1998, 271-273, 72-77.
[http://dx.doi.org/10.1016/S0925-8388(98)00027-9]
[12]
Lu, Y.; Miller, M.J. Syntheses and studies of multiwarhead siderophore-5-fluorouridine conjugates. Bioorg. Med. Chem., 1999, 7(12), 3025-3038.
[http://dx.doi.org/10.1016/S0968-0896(99)00248-5] [PMID: 10658609]
[13]
Grady, R.W.; Peterson, C.M.; Jones, R.L.; Graziano, J.H.; Bhargava, K.K.; Berdoukas, V.A.; Kokkini, G.; Loukopoulos, D.; Cerami, A. Rhodotorulic acid-investigation of its potential as an iron-chelating drug. Pharmacol. Exp. Ther., 1979, 209, 342-348.
[14]
Atkin, C.L.; Neilands, J.B. Rhodotorulic acid, a diketopiperazine dihydroxamic acid with growth-factor activity. I. Isolation and characterization. Biochemistry, 1968, 7(10), 3734-3739.
[http://dx.doi.org/10.1021/bi00850a054] [PMID: 4971459]
[15]
Atkin, C.L.; Neilands, J.B.; Phaff, H.J. Rhodotorulic acid from species of Leucosporidium, Rhodosporidium, Rhodotorula, Sporidiobolus, and Sporobolomyces, and a new alanine-containing ferrichrome from Cryptococcus melibiosum. J. Bacteriol., 1970, 103(3), 722-733.
[http://dx.doi.org/10.1128/jb.103.3.722-733.1970] [PMID: 5529038]
[16]
Brich, L.E.; Ruddat, M. Extracellular Accumulation of rhodotorulic acid in strains of Microbotryum violaceum. Int. J. Plant Sci., 1998, 159, 213-220.
[http://dx.doi.org/10.1086/297541]
[17]
Van der Helm, D.; Winkelmann, G. Hydroxamates and polycarboxylates as iron transport agents (Siderophores) in fungi. In: Metal Ions in Fungi, 1st ed.; CRC Press, 1994.
[18]
Pecoraro, L.; Wang, X.; Shah, D.; Song, X.; Kumar, V.; Shakoor, A.; Tripathi, K.; Ramteke, P.W.; Rani, R. J. Fungi (Basel), 2022, 8, 1-28.
[19]
De Luca, N.G.; Wood, P.M. Iron uptake by fungi: Contrasted mechanisms with internal or external reduction. Adv. Microb. Physiol., 2000, 43, 39-74.
[http://dx.doi.org/10.1016/S0065-2911(00)43002-X] [PMID: 10907554]
[20]
Neilands, J.B.; Konopka, K.; Schwyn, B.; Francis, R.T.; Paw, B.H.; Bagg, A. Iron Transport in Microbes; Plants and Animals, 1987, pp. 1-33.
[21]
Anke, T.; Diekmann, H. Biosynthesis of sideramines in fungi. Rhodotorulic acid synthetase from extracts of Rhodotorula glutinis. FEBS Lett., 1972, 27(2), 259-262.
[http://dx.doi.org/10.1016/0014-5793(72)80635-5] [PMID: 4677112]
[22]
Leong, S.A.; Winkelmann, G. Molecular biology of iron transport in fungi. Met. Ions Biol. Syst., 1998, 35, 147-186.
[PMID: 9444761]
[23]
Akres, H.; Llinas, M.; Neilands, J.B. Protonated amino acid precursor studies on rhodotorulic acid biosynthesis in deuterium oxide media. Biochemistry, 1972, 12, 2283-2291.
[http://dx.doi.org/10.1021/bi00762a012]
[24]
Makarova, E.N.; Grigoryan, D.T. [Effect of urea and amino acids of the ornithine cycle on the biomass accumulation and amino acids synthesis by Candida guilliermondii]. Prikl. Biokhim. Mikrobiol., 1975, 11(3), 322-325.
[PMID: 1208387]
[25]
Calvente, V.; de Orellano, M.E.; Sansone, G.; Benuzzi, D.; Sanz de Tosetti, M.I. Effect of nitrogen source and pH on siderophore production by Rhodotorula strains and their application to biocontrol of phytopathogenic moulds. J. Ind. Microbiol. Biotechnol., 2001, 26(4), 226-229.
[http://dx.doi.org/10.1038/sj.jim.7000117]
[26]
Andersen, D.; Renshaw, J.C.; Wiebe, M.G. Rhodotorulic acid production by Rhodotorula mucilaginosa. Mycol. Res., 2003, 107(8), 949-956.
[http://dx.doi.org/10.1017/S0953756203008220] [PMID: 14531617]
[27]
Das, A.; Prasad, R.; Srivastava, A.; Giang, P.H.; Bhatnagar, K.; Varma, A. Fungal siderophores: Structure, functions and regulation. Soc. Biol., 2007, 12, 1-42.
[http://dx.doi.org/10.1007/978-3-540-71160-5_1]
[28]
Matzanke, B.F. Iron storage in fungi. Winkelmann, G.; Wing, DR. In: Metal Ions in Fungi; Marcel Dekker: NY, 1994; pp. 179-214.
[29]
Carrano, C.J.; Raymond, K.N. Coordination chemistry of microbial iron transport compounds: Rhodotorulic acid and iron uptake in Rhodotorula pilimanae. J. Bacteriol., 1978, 136(1), 69-74.
[http://dx.doi.org/10.1128/jb.136.1.69-74.1978] [PMID: 30750]
[30]
Müller, G.; Barclay, S.J.; Raymond, K.N. The mechanism and specificity of iron transport in Rhodotorula pilimanae probed by synthetic analogs of rhodotorulic acid. J. Biol. Chem., 1985, 260(26), 13916-13920.
[http://dx.doi.org/10.1016/S0021-9258(17)38663-5] [PMID: 4055765]
[31]
Matzanke, B.F.; Bill, E.; Trautwein, A.X.; Winkelmann, G. Siderophores as iron storage compounds in the yeastsRhodotorula minuta and Ustilago sphaerogena detected by in vivo Mössbauer spectroscopy. Hyperfine Interact., 1990, 58(1-4), 2359-2364.
[http://dx.doi.org/10.1007/BF02398344]
[32]
Hantke, K. Identification of an iron uptake system specific for coprogen and rhodotorulic acid in Escherichia coli K12. Mol. Gen. Genet., 1983, 191(2), 301-306.
[http://dx.doi.org/10.1007/BF00334830] [PMID: 6353165]
[33]
Winkelmann, G. Handbook of microbial iron chelates. 1991, pp. 65-105.
[34]
Noinaj, N.; Guillier, M.; Barnard, T.J.; Buchanan, S.K. TonB-dependent transporters: Regulation, structure, and function. Annu. Rev. Microbiol., 2010, 64(1), 43-60.
[http://dx.doi.org/10.1146/annurev.micro.112408.134247] [PMID: 20420522]
[35]
Boukhalfa, H.; Crumbliss, A.L. Chemical aspects of siderophore mediated iron transport. Biometals, 2002, 15(4), 325-339.
[http://dx.doi.org/10.1023/A:1020218608266] [PMID: 12405526]
[36]
Carrano, C.J.; Cooper, S.R.; Raymond, K.N. Coordination chemistry of microbial iron transport compounds. 11. Solution equilibriums and electrochemistry of ferric rhodotorulate complexes. J. Am. Chem. Soc., 1979, 101(3), 599-604.
[http://dx.doi.org/10.1021/ja00497a019]
[37]
Müller, G.; Isowa, Y.; Raymond, K.N. Stereospecificity of siderophore-mediated iron uptake in Rhodotorula pilimanae as probed by enantiorhodotorulic acid and isomers of chromic rhodotorulate. J. Biol. Chem., 1985, 260(26), 13921-13926.
[http://dx.doi.org/10.1016/S0021-9258(17)38664-7] [PMID: 4055766]
[38]
Müller, G.; Matzanke, B.F.; Raymond, K.N. Iron transport in Streptomyces pilosus mediated by ferrichrome siderophores, rhodotorulic acid, and enantio-rhodotorulic acid. J. Bacteriol., 1984, 160(1), 313-318.
[http://dx.doi.org/10.1128/jb.160.1.313-318.1984] [PMID: 6480558]
[39]
Carrano, C.J.; Raymond, K.N. Coordination chemistry of microbial iron transport compounds. 10. Characterization of the complexes of rhodotorulic acid, a dihydroxamate siderophore. J. Am. Chem. Soc., 1978, 100(17), 5371-5374.
[http://dx.doi.org/10.1021/ja00485a019]
[40]
Carrano, C.J.; Raymond, K.N. Synthesis and characterization of iron complexes of rhodotorulic acid: A novel dihydroxamate siderophore and potential chelating drug. J. Chem. Soc. Chem. Commun., 1978, 12(12), 501-502.
[http://dx.doi.org/10.1039/c39780000501]
[41]
Spasojević, I.; Armstrong, S.K.; Brickman, T.J.; Crumbliss, A.L. Electrochemical behavior of the Fe(III) complexes of the cyclic hydroxamate siderophores alcaligin and desferrioxamine E. Inorg. Chem., 1999, 38(3), 449-454.
[http://dx.doi.org/10.1021/ic980635n] [PMID: 11673947]
[42]
Zaiter, N.; Krad, I.; Roukos, R. Thermodynamic studies of iron(III) complex of some new dihydroxamic acids model of rhodotorulic acid. Inorg. Chim. Acta, 2018, 482, 187-194.
[http://dx.doi.org/10.1016/j.ica.2018.06.016]
[43]
Isowa, Y.; Takashima, T.; Ohmori, M.; Kurita, H.; Sato, M.; Mori, K. Synthesis of rhodotorulic acid. Bull. Chem. Soc. Jpn., 1972, 45(5), 1467-1471.
[http://dx.doi.org/10.1246/bcsj.45.1467]
[44]
Fuji, T.; Hatanaka, Y. A synthesis of rhodotorulic acid. Tetrahedron, 1973, 29, 3825-3831.
[http://dx.doi.org/10.1016/0040-4020(73)80202-9]
[45]
Lee, B.H.; Gerfen, G.J.; Miller, M.J. Constituents of microbial iron chelators. Alternate syntheses of delta-N-hydroxy-L-ornithine derivatives and applications to the synthesis of rhodotorulic acid. J. Org. Chem., 1984, 49(13), 2418-2423.
[http://dx.doi.org/10.1021/jo00187a023]
[46]
Nakao, M.; Fukayama, S.; Kitaike, S.; Sano, S. Heterocycles, 2015, 90, 1309-1316.
[http://dx.doi.org/10.3987/COM-14-S(K)67]
[47]
Lee, B.H.; Miller, M.J.; Prody, C.A.; Neilands, J.B. Artificial siderophores. 2. Syntheses of trihydroxamate analogs of rhodotorulic acid and their biological iron transport capabilities in Escherichia coli. J. Med. Chem., 1985, 28(3), 323-327.
[http://dx.doi.org/10.1021/jm00381a011] [PMID: 3156249]
[48]
Nakao, M. Development of novel functional molecules based on the molecular structure characteristics of diketopiperazines. Yakugaku Zasshi, 2017, 137(12), 1505-1516.
[http://dx.doi.org/10.1248/yakushi.17-00176] [PMID: 29199259]
[49]
Calvente, V.; Benuzzi, D.; de Tosetti, M.I.S. Antagonistic action of siderophores from Rhodotorula glutinis upon the postharvest pathogen Penicillium expansum. Int. Biodeterior. Biodegradation, 1999, 43(4), 167-172.
[http://dx.doi.org/10.1016/S0964-8305(99)00046-3]
[50]
Snowdon, A.L. A colour atlas of post-harvest diseases and disorders of fruits and vegetables: General introduction and fruits; Wolfe, 1990.
[51]
Chand-Goyal, T.; Spotts, R.A. Control of postharvest pear diseases using natural saprophytic yeast colonists and their combination with a low dosage of thiabendazole. Postharvest Biol. Technol., 1996, 7(1-2), 51-64.
[http://dx.doi.org/10.1016/0925-5214(95)00031-3]
[52]
Sansone, G.; Rezza, I.; Calvente, V.; Benuzzi, D.; Tosetti, M.I.S. Control of botrytis cinerea strains resistant to iprodione in apple with rhodotorulic acid and yeasts. Postharvest Biol. Technol., 2005, 35(3), 245-251.
[http://dx.doi.org/10.1016/j.postharvbio.2004.09.005]
[53]
Miller, G.W.; Pushnik, J.C.; Browne, J.C.; Emery, T.E.; Jolley, V.D.; Warnick, K.Y. Biochemistry of Metal Micronutrients in the Rhizosphere. CRC Press; 1994.
[54]
Johnson, G.V.; Lopez, A.; La Valle Foster, N. Reduction and transport of Fe from siderophores. Plant Soil, 2002, 241(1), 27-33.
[http://dx.doi.org/10.1023/A:1016007708926]
[55]
Rӧmheld, V.; Marschner, H. Mobilization of iron in the rhizosphere of different plant species. Adv. Plant Nutr, 1986, 2, 155-204.
[56]
Fernandez-Scavino, A.; Pedraza, R.O. The role of siderophores in plant growth-promoting bacteria. Bacteria in Agrobiology: Crop Productivity, 2013, 265-285.
[57]
Miller, G.W. Treatment of plant chlorosis with rhodotorulic acid. EP Patent 0197225A2, 1989.
[58]
Lee, B.H.; Pan, T.M. Dimerumic acid, a novel antioxidant identified from Monascus-fermented products exerts chemoprotective effects: Mini review. J. Funct. Foods, 2013, 5(1), 2-9.
[http://dx.doi.org/10.1016/j.jff.2012.11.009]
[59]
Khan, W.; Regmi, O.; Panda, B.P. Enrichment of dimerumic acid in Monascus-fermented rice and its in vivo antioxidant activity. Food Front., 2021, 2(4), 547-556.
[http://dx.doi.org/10.1002/fft2.108]
[60]
Taira, J.; Miyagi, C.; Aniya, Y. Dimerumic acid as an antioxidant from the mold, Monascus anka: The inhibition mechanisms against lipid peroxidation and hemeprotein- mediated oxidation. Biochem. Pharmacol., 2002, 63(5), 1019-1026.
[http://dx.doi.org/10.1016/S0006-2952(01)00923-6] [PMID: 11911855]
[61]
Sekine, S.; Yano, K.; Saeki, J.; Hashimoto, N.; Fuwa, T.; Horie, T. Oxidative stress is a triggering factor for LPS-induced Mrp2 internalization in the cryopreserved rat and human liver slices. Biochem. Biophys. Res. Commun., 2010, 399(2), 279-285.
[http://dx.doi.org/10.1016/j.bbrc.2010.07.069]
[62]
Yano, K.; Sekine, S.; Nemoto, K.; Fuwa, T.; Horie, T. The effect of dimerumic acid on LPS-induced downregulation of Mrp2 in the rat. Biochem. Pharmacol., 2010, 80(4), 533-539.
[http://dx.doi.org/10.1016/j.bcp.2010.04.036] [PMID: 20457138]
[63]
Yamaishiro, J.; Sumihiro, S.; Toru, F.; Toshiharu, H. Dimerumic acid protected oxidative stress-induced cytotoxicity in isolated rat hepatocytes. Cell Biol. Toxicol., 2008, 24, 283-290.
[64]
Lee, B.H.; Hsu, W.H.; Hsu, Y.W.; Pan, T.M. Suppression of dimerumic acid on hepatic fibrosis caused from carboxymethyl-lysine (CML) by attenuating oxidative stress depends on Nrf2 activation in hepatic stellate cells (HSCs). Food Chem. Toxicol., 2013, 62, 413-419.
[http://dx.doi.org/10.1016/j.fct.2013.09.007] [PMID: 24036144]
[65]
Aniya, Y.; Ohtani, I.I.; Higa, T.; Miyagi, C.; Gibo, H.; Shimabukuro, M.; Nakanishi, H.; Taira, J. Dimerumic acid as an antioxidant of the mold, Monascus Anka. Free Radic. Biol. Med., 2000, 28(6), 999-1004.
[http://dx.doi.org/10.1016/S0891-5849(00)00188-X] [PMID: 10802232]
[66]
Lai, J.R.; Ke, B.J.; Hsu, Y.W.; Lee, C.L. Dimerumic acid and deferricoprogen produced by Monascus purpureus attenuate liquid ethanol diet-induced alcoholic hepatitis via suppressing NF-κB inflammation signalling pathways and stimulation of AMPK-mediated lipid metabolism. J. Funct. Foods, 2019, 60, 103393.
[http://dx.doi.org/10.1016/j.jff.2019.05.049]
[67]
Lee, B.H.; Hsu, W.H.; Hsu, Y.W.; Pan, T.M. Dimerumic acid attenuates receptor for advanced glycation endproducts signal to inhibit inflammation and diabetes mediated by Nrf2 activation and promotes methylglyoxal metabolism into d-lactic acid. Free Radic. Biol. Med., 2013, 60, 7-16.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.01.030] [PMID: 23434766]
[68]
Lee, B.H.; Hsu, W.H.; Hsu, Y.W.; Pan, T.M. Dimerumic acid protects pancreas damage and elevates insulin production in methylglyoxal-treated pancreatic RINm5F cells. J. Funct. Foods, 2013, 5(2), 642-650.
[http://dx.doi.org/10.1016/j.jff.2012.12.007]
[69]
Ho, B.Y.; Wu, Y.M.; Chang, K.J.; Pan, T.M. Dimerumic acid inhibits SW620 cell invasion by attenuating H2O2-mediated MMP-7 expression via JNK/C-Jun and ERK/C-Fos activation in an AP-1-dependent manner. Int. J. Biol. Sci., 2011, 7(6), 869-880.
[http://dx.doi.org/10.7150/ijbs.7.869] [PMID: 21814482]
[70]
Tseng, W.T.; Hsu, Y.W.; Pan, T.M. Dimerumic acid and deferricoprogen activate ak mouse strain thymoma/heme oxygenase-1 pathways and prevent apoptotic cell death in 6-hydroxydopamine-induced SH-SY5Y cells. J. Agric. Food Chem., 2016, 64(30), 5995-6002.
[http://dx.doi.org/10.1021/acs.jafc.6b01551] [PMID: 27431098]
[71]
Tseng, W.T. Neuroprotective effects of dimerumic acid and deferricoprogen from Monascus purpureus NTU 568-fermented rice against 6-hydroxydopamine-induced oxidative stress and apoptosis in differentiated pheochromocytoma PC-12 cells. Pharm. Biol., 2016, 54, 1434-1444.
[http://dx.doi.org/10.3109/13880209.2015.1104698] [PMID: 26794209]
[72]
Krasnoff, S.B.; Keresztes, I.; Donzelli, B.G.G.; Gibson, D.M. Metachelins, mannosylated and N-oxidized coprogen-type siderophores from Metarhizium robertsii. J. Nat. Prod., 2014, 77(7), 1685-1692.
[http://dx.doi.org/10.1021/np500300s] [PMID: 24992511]
[73]
Krasnoff, S.B.; Howe, K.J.; Heck, M.L.; Donzelli, B.G.G. Siderophores from the entomopathogenic fungus Beauveria bassiana. J. Nat. Prod., 2020, 83(2), 296-304.
[http://dx.doi.org/10.1021/acs.jnatprod.9b00698] [PMID: 32058711]
[74]
Kalansuriya, P.; Quezada, M.; Espósito, B.P.; Capon, R.J. Talarazines A–E: noncytotoxic iron(III) chelators from an Australian mud dauber wasp-associated fungus, Talaromyces sp. (CMB-W045). J. Nat. Prod., 2017, 80(3), 609-615.
[http://dx.doi.org/10.1021/acs.jnatprod.6b00889] [PMID: 28058837]
[75]
Ouchi, T.; Watanabe, Y.; Nonaka, K.; Muramatsu, R.; Noguchi, C.; Tozawa, M.; Hokari, R.; Ishiyama, A.; Koike, R.; Matsui, H.; Asami, Y.; Inahashi, Y.; Ishii, T.; Teruya, T.; Iwatsuki, M.; Hanaki, H.; Ōmura, S. Clonocoprogens A, B and C, new antimalarial coprogens from the Okinawan fungus Clonostachys compactiuscula FKR-0021. J. Antibiot., 2020, 73(6), 365-371.
[http://dx.doi.org/10.1038/s41429-020-0292-7] [PMID: 32139881]