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User:Edison Tenecela/sandbox/chm275

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Edison Tenecela/sandbox/chm275
Names
IUPAC name
N-{[(3R)-5-chloro-8-hydroxy-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-7-yl]carbonyl}-Lphenylalanine
Other names
(R)-N- [(5-Chloro- 3,4-dihydro- 8-hydroxy- 3-methyl- 1-oxo- 1H-2-benzopyran-7-yl) -carbonyl]- L- phenylalanine
(−)-N- [(5-Chloro- 8-hydroxy- 3-methyl- 1-oxo- 7-isochromanyl) carbonyl]- 3-phenylalanine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
  • InChI=1S/C20H18ClNO6/c1-10-7-12-14(21)9-13(17(23)16(12)20(27)28-10)18(24)22-15(19(25)26)8-11-5-3-2-4-6-11/h2-6,9-10,15,23H,7-8H2,1H3,(H,22,24)(H,25,26)/t10-,15+/m1/s1 checkY
    Key: RWQKHEORZBHNRI-BMIGLBTASA-N checkY
  • InChI=1/C20H18ClNO6/c1-10-7-12-14(21)9-13(17(23)16(12)20(27)28-10)18(24)22-15(19(25)26)8-11-5-3-2-4-6-11/h2-6,9-10,15,23H,7-8H2,1H3,(H,22,24)(H,25,26)/t10-,15+/m1/s1
    Key: RWQKHEORZBHNRI-BMIGLBTABQ
  • O=C(O)[C@@H](NC(=O)c1c(O)c2c(c(Cl)c1)C[C@H](OC2=O)C)Cc3ccccc3
Properties
C20H18ClNO6
Molar mass 403.813
Melting point 169 °C (336 °F; 442 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Tracking categories (test):

Ochratoxin A (OTA), is a white powdered polyketide mycotoxin whose name derives from the fungal species Aspergillus Ochraceus.[1] It is produced by different Aspergillus and Penicillium species and is considered one of the most abundant food-contaminating mycotoxins.[2] OTA is found in water-damaged houses, heating ducts,[3][4] and human exposure can occur through consumption of contaminated food products, particularly grain and pork, as well as coffee, wine grapes, and dried grapes.[5][6][7] Studies on several organisms have shown that OTA can have several nephrotoxic, hepatotoxic, neurotoxic, teratogenic and immunologic effects with large specific toxicological differences depending on sex, species, and cellular type.[6][8] The median lethal dose (oral LD50) for OTA in (mg/kg) body weight is 0.2 for dogs, 1 for pigs, 20-30 for rats and 46-58 for mice.[9] As a reference point using rats, it is more poisonous than nicotine (50mg/kg), and less toxic than cyanide (10mg/kg).[10]


Chemistry of Ochratoxin A

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Ochratoxin A (OTA) is a chiral polyketide derived from the dihydrocoumarins family. The isocoumarin moiety of OTA contains a para-chlorophenolic group amide linked to L-phenylalanine. OTA is a weak organic acid with a pKa value of 7.1 for the carboxyl group and 7.9 for the hydroxyl group. Once in an organism, the compound produces a variety of metabolites that range from dechloro analogs to tyrosine, serine and lysine analogs by replacement of the L-phenylalanine.[8] Of these metabolites, certain derived products such as a hydroquinone molecule have shown to have toxicological properties involving the formation of covalent DNA adducts.[11]

In terms of solubility, it is water-soluble as a sodium salt. Under acidic and neutral pH, it is moderately soluble in polar organic solvents (alcohols, ketones, chloroform) and under basic pH, it tends to be soluble under all types of conditions.[8] Furthermore, studies have shown a high stability to acidity and high temperatures,[12] even at temperatures as high as 250°C.[13] However, degradation was observed when OTA was treated with sodium hypochlorite (bleach) followed by an alternative treatment with fluorescent light.[8]

Impact on human and animal health

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Carcinogenicity

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Ochratoxin A is potentially carcinogenic to humans (Group 2B), and has been shown to be weakly mutagenic, possibly by induction of oxidative DNA damage.[14]

The evidence in experimental animals is sufficient to indicate carcinogenicity of ochratoxin A. It was tested for carcinogenicity by oral administration in mice and rats. It slightly increased the incidence of hepatocellular carcinomas in mice of each sex.[15] and produced renal adenomas and carcinomas in male mice and in rats (carcinomas in 46% of males and 5% of females).[16] In humans, very little histology data are available, so a relationship between ochratoxin A and renal cell carcinoma has not been found. However, the incidence of transitional cell (urothelial) urinary cancers seems abnormally high in Balkan endemic nephropathy patients, especially for the upper urinary tract.[17] The molecular mechanism of ochratoxin A carcinogenicity has been under debate due to conflicting literature, however this mycotoxin has been proposed to play a major role in reducing antioxidant defenses.[18]

Neurotoxicity

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Ochratoxin A has a strong affinity for the brain, especially the cerebellum (Purkinje cells), ventral mesencephalon, and hippocampal structures.[19] The affinity for the hippocampus could be relevant to the pathogenesis of Alzheimer's disease, and subchronic administration to rodents induces hippocampal neurodegeneration. Ochratoxin causes acute depletion of striatal dopamine, which constitutes the bed of Parkinson's disease, but it did not cause cell death in any of brain regions examined.[20] Teams from Zheijiang Univ. and Kiel Univ. hold that ochratoxin may contribute to Alzheimer's and to Parkinson's diseases. Nonetheless, their study was performed in vitro and may not extrapolate to humans.[21] The developing brain is very susceptible to ochratoxin, hence the need for caution during pregnancy.[22]

Immunosuppression and immunotoxicity

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Ochratoxin A can cause immunosuppression and immunotoxicity in animals. The toxin's immunosuppressant activity in animals may include depressed antibody responses, reduced size of immune organs (such as the thymus, spleen, and lymph nodes), changes in immune cell number and function, and altered cytokine production. Immunotoxicity probably results from cell death following apoptosis and necrosis, in combination with slow replacement of affected immune cells due to inhibition of protein synthesis.[2]

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Balkan endemic nephropathy (BEN), a slowly progressive renal disease, appeared in the middle of the 20th century, highly localized around the Danube, but only hitting certain households. Patients over the years develop renal failure that requires dialysis or transplantation. The initial symptoms are those of a tubulointerstitial nephritis of the sort met with after toxic aggressions to the proximal convoluted tubules. Such proximal tubule nephropathies can be induced by aluminium (e.g. in antiperspirants), antibiotics (vancomycin, aminosides), tenofovir (for AIDS), and cisplatin[citation needed]. Their symptoms are well known to nephrologists: glycosuria without hyperglycemia, microalbuminuria, poor urine concentration capacity, impaired urine acidification, and yet long-lasting normal creatinine clearance.[23] In BEN, renal biopsy shows acellular interstitial fibrosis, tubular atrophy, and karyomegaly in proximal convoluted tubules.[24] A number of descriptive studies have suggested a correlation between exposure to ochratoxin A and BEN, and have found a correlation between its geographical distribution and a high incidence of, and mortality from, urothelial urinary tract tumours.[25] However, insufficient information is currently available to conclusively link ochratoxin A to BEN.[26] The toxin may require synergistic interactions with predisposing genotypes or other environmental toxicants to induce this nephropathy.[27] Ochratoxin possibly is not the cause of this nephropathy, and many authors are in favor of aristolochic acid, that is contained in a plant: birthwort (Aristolochia clematitis). Nevertheless, although many of the pieces of scientific evidence are lacking and/or need serious re-evaluation, it remains that ochratoxin, in pigs, demonstrates direct correlation between exposure and onset and progression of nephropathy.[28] This porcine nephropathy[29] bears typical signs of toxicity to proximal tubules: loss of ability to concentrate urine, glycosuria, and histological proximal tubule degeneration.

Other nephropathies, although not responding to the "classical" definition of BEN, may be linked to ochratoxin. Thus, this could in certain circumstances be the case for focal segmental glomerulosclerosis after inhalational exposure: such a glomerulopathy with noteworthy proteinuria has been described[30] in patients with very high urinary ochratoxin levels (around 10 times levels that can be met with in "normal" subjects, i.e. around 10 ppb or 10 ng/ml).

Food animal industry impact

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Ochratoxin-contaminated feed has its major economic impact on the poultry industry. Chickens, turkeys, and ducklings are susceptible to this toxin. Clinical signs of avian ochratoxicosis generally involve reduction in weight gains, poor feed conversion, reduced egg production, and poor egg shell quality.[31] Economic losses occur also in swine farms, linked to nephropathy and costs for the disposal of carcasses.

Toxicity does not seem to constitute a problem in cattle, as the rumen harbors protozoa that hydrolyze OTA.[32] However, contamination of milk is a possibility.[citation needed]

Dietary guidelines

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Concentrations of ochratoxin in usual foods
Source Median
in μg/kg
of food 		Median
in ng/kg
of food 		Weight
in kg 		Diet 1 Diet 1+
Liquorice extract 26.30 26,300.00
Ginger 5.50 5,500.00 0.005 27.50
Nutmeg 2.27 2,265.00 0.005 11.33
Paprika 1.32 1,315.00 0.005 6.58
Pig liver 1.10 1,100.00
Ginseng 1.10 1,100.00
Raisins dry 0.95 950.00 0.1 95.00
Pig kidney 0.80 800.00 0.3 160.00
Liquorice confectionery 0.17 170.00
Coffee 0.13 125.00 0.3 37.50
Cereals 0.09 87.50 0.5 43.75
Peanuts 0.08 79.00 0.2 15.80
Wine 0.05 50.00 0.5 25.00
Pulses 0.05 49.50 0.5 24.75
Beer 0.05 49.00
Salami 0.05 49.00 0.3 14.70
Total in ng 286.10 461.90

EFSA established in 2006 the "tolerable weekly intake" (TWI) of ochratoxin A (on advice of the Scientific Panel on Contaminants in the Food Chain) at 120 ng/kg.,[33] equivalent to a tolerable daily intake (TDI) of 14 ng/kg. Other organizations have established even lower limits for intake of ochratoxin A, based on the consumption habits of the population.[34] For USA, the FDA considers a TDI of 5 ng/kg. In the US, mean body weight for men is 86 kg, and for women 74 kg.[citation needed] Hence, the TDI for men is 430 ng and for women is 370 ng. In the joined table "weight in kg" is the weight eaten per day of each of the listed foodstuffs. Diet 1, with small quantities of ginger, nutmeg, and paprika, a good serving of dry raisins, a reasonable amount of coffee, cereals, wine, pulses, and salami, amounts to a safe diet (as for ochratoxin, at least), with 286 ng per day. However, it would be easy to go into excessive levels (Diet 1+), just by eating 200 g of pig kidney and 200 g of peanuts, which would lead to a total of nearly 462 ng of ochratoxin. This shows how delicate a safe diet can be.

Tolerable daily intake 5 ng/kg
Gender Weight
in kg 		Tolerable OTA
in ng
male 86 430
female 74 370

Although ochratoxin A is not held as of today as responsible for renal cell carcinoma (RCC), the most frequent renal cancer, it is frequently written that dietary pattern might decrease or increase the risk of RCC. A Uruguayan case-control study [35] correlates intake of meat with occurrence of RCC. A very large prospective cohort in Sweden [36] explores correlations between RCC occurrence, diets rich in vegetables and poultry (so-called "healthy diets"), and diets rich in meat (especially processed meat: salami, black pudding). The thesis defended is that more fruit and vegetables might have a protective role. Fruit (except raisins and dried fruit) are very poor in ochratoxin, and processed meat can be rich in ochratoxin.

Dermal exposure

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Ochratoxin A can permeate through the human skin.[37] Although no significant health risk is expected after dermal contact in agricultural or residential environments, skin exposure to ochratoxin A should nevertheless be limited.

Genetic resistance

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In 1975 Woolf et al[38] proposed that the inherited disorder Phenylketonuria protects against ochratoxin A poisoning through the production of high levels of phenylalanine. Ochratoxin is a competitive inhibitor of phenylalanine in the phenylalanyl-tRNA-synthetase-catalyzed reaction thus preventing protein synthesis, which can be reversed by introducing phenylalanine, which is in excess in PKU individuals.[39]

Biosynthesis of Ochratoxin A

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Despite its importance as a mycotoxin, the biosynthetic pathway for OTA is yet to be fully established. A paper written by Huff and Hamilton[1] shows the biosynthesis of Ochratoxin A as a 3-part process: synthesis and activation of both the isocoumarin and phenylalanine portions of the future OTA, and the final nucleophilic acyl substitution reaction between these two components.

The isocoumarin portion of OTA is produced through a series of steps involving the polyketide pathway. Acetyl-CoA and malonyl-CoA molecules condense with polyketide synthase (PKS) and form a pentaketide which undergoes a cyclization/aromatization reaction forming mellein. Due to the ortho-directing nature of the phenolic group, a carboxy functional group is added to carbon 7 of the isocoumarin component forming Ochratoxin β (OT β). A chloroperoxidase then adds chlorine to the para position of the phenolic group as would be expected due to the presence of the ortho blocking 7-carboxy. The chlorinated molecule is then known as Ochratoxin α (OTα). Due to the deactivating nature of halogenated aromatic ring systems, in order to properly activate the isocoumarin portion of the future OTA molecule, a phosphorylation step occurs using ATP. This leads to the formation of a mixed anhydride priming it for a future nucleophilic acyl substitution reaction with the phenylalanine component.

The synthesis of the phenylalanine portion of OTA is achieved via the shikimic acid pathway. The pathway starts with a 7-carbon aldonic acid which then forms shikimic acid until finally reaching phenylalanine via a transamination step from phenylpyruvic acid. Nevertheless, amino acids tend to be in the zwitterion form in biological systems, remaining unreactive for acyl substitutions. As a result, the carboxy group of phenylalanine is converted to an ethyl ester priming and activating the phenylalanine component for an upcoming acyl reaction with the isocoumarin component.

The last step consists of the nucleophilic acyl substitution reaction between the isocoumarin and phenylalanine portions of the future OTA molecule. After the acyl activation of OTα to a mixed anhydride, the leaving phosphate group is displaced by the amine group of the phenylalanine ester. The product formed is known as Ochratoxin C (OTC), which is then de-esterified by an esterase or transesterification mechanism forming OTA.[1]

There is still ongoing research on this topic. Studies, for example, have utilized PCR and subtractive PCR for the analysis of several polyketide synthase (PKS) genes.[40][41] Degenerated primers have also been used to target KS domains, the most conservative domain of the PKS genes, proving succesful when utilized in OTA fungal producers.[42] There is still much work needed to be done, all in hopes of a better understanding of the underlying molecular biosynthetic pathway of OTA.

 

See also

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References

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  1. ^ a b c "Mycotoxins – Their Biosynthesis in Fungi: Ochratoxins – Metabolites of Combined Pathways". doi:10.4315/0362-028X-42.10.815. {{cite journal}}: Cite journal requires |journal= (help)
  2. ^ a b Al-Anati L, Petzinger E (2006). "Immunotoxic activity of ochratoxin A". J. Vet. Pharmacol. Ther. 29 (2): 79–90. doi:10.1111/j.1365-2885.2006.00718.x. PMID 16515661.
  3. ^ Polizzi V, et al. (2009). "Fungi, mycotoxins and volatile organic compounds in mouldy interiors from water-damaged buildings". Journal of Environmental Monitoring. 11: 1849–1858.
  4. ^ Richard JL; at al. (1999). "The occurrence of ochratoxin A in dust collected from a problem household". Mycopathologia. 146 (2): 99–103. doi:10.1023/A:1007056627296. PMID 10822509.
  5. ^ Pfohl-Leszkowicz A, Manderville RA (2007). "Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans". Mol Nutr Food Res. 51 (1): 61–99. doi:10.1002/mnfr.200600137. PMID 17195275.
  6. ^ a b O'Brien E, Dietrich DR (2005). "Ochratoxin A: the continuing enigma". Crit. Rev. Toxicol. 35 (1): 33–60. doi:10.1080/10408440590905948. PMID 15742902.
  7. ^ Blesa J, et al. (2006). "Factors affecting the presence of ochratoxin A in wines". Critical Reviews in Food Science and Nutrition. 46 (6): 473–8. doi:10.1080/10408390500215803. PMID 16864140.
  8. ^ a b c d "Ochratoxin A: General Overview and Actual Molecular Status". doi:10.3390/toxins2040461. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: unflagged free DOI (link)
  9. ^ "Ochratoxin A". Wiley Library. Wiley. Retrieved 5 May 2020.
  10. ^ Trautmann, Nancy (2001). Assessing toxic risk (Student ed.). NSTA Press. ISBN 0873552229. Retrieved 5 May 2020.
  11. ^ "Genotoxicity of the hydroquinone metabolite of ochratoxin A: structure-activity relationships for covalent DNA adduction". doi:10.1021/tx060138g. {{cite journal}}: Cite journal requires |journal= (help)
  12. ^ "Ochratoxin A". Pubchem Database. National Center for Biotechnology Information. Retrieved 18 April 2020.
  13. ^ "Thermostability of Ochratoxin A in wheat under two moisture conditions". PMID 7793917. {{cite journal}}: Cite journal requires |journal= (help)
  14. ^ Palma N, et al. (2007). "Ochratoxin A-Induced Mutagenesis in Mammalian Cells Is Consistent with the Production of Oxidative Stress". Chemical Research in Toxicology. 20 (7): 1031–1037. doi:10.1021/tx700027j. PMC 2367102. PMID 17567156.
  15. ^ Bendele AM, et al. (1985). "Ochratoxin A Carcinogenesis in the (C57BL/6J X C3H) F1mouse". J Natl Cancer Inst. 75 (4): 733–42. PMID 3862905.
  16. ^ Gary A. Boorman. "Toxicology and Carcinogenesis studies of Ochratoxin A in F344/N rats". National Toxicology Program, May 1989, NTP TR 358.
  17. ^ Basic-Jukic N, et al. (2007). "Renal transplantation in patients with Balkan endemic nephropathy". Transplant Proc. 39 (5): 1432–1435. doi:10.1016/j.transproceed.2006.11.019. PMID 17580155.
  18. ^ C. Cavin; T. Delatour; M. Marin-Kuan; D. Holzhauser; L. Higgins; C. Bezencon (2007). "REduction in antioxidant defences may contribute to ochratoxin A toxicity and carcinogenicity". Toxicological Sciences. 96 (1): 30–39. doi:10.1093/toxsci/kfl169. PMID 17110534.
  19. ^ Belmadani A, et al. (1999). "Selective toxicity of ochratoxin A in primary cultures from different brain regions". Arch Toxicol. 73 (2): 108–114. doi:10.1007/s002040050594. PMID 10350191.
  20. ^ Sava V, et al. (2006). "Acute neurotoxic effects of the fungal metabolite ochratoxin A". Neurotoxicology. 27 (1): 82–92. doi:10.1016/j.neuro.2005.07.004. PMID 16140385.
  21. ^ Xiangnan Zhang; et al. (2009). "Ochratoxin A induces apoptosis in neuronal cells". Genes Nutr. 4 (1): 41–48. doi:10.1007/s12263-008-0109-y. PMC 2654052. PMID 19148691.
  22. ^ Kunio Doi; Koji Uetsuka (2011). "Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways". International Journal of Molecular Sciences. 12 (8): 5213–5327. doi:10.3390/ijms12085213. PMC 3179161. PMID 21954354.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ Aleckovic M, et al. (2010). "Glomerular filtration rate in examined population of Bosnian Posavina – region of Balkan Endemic Nephropathy". Bosn J Basic Med Sci. 10 (3–4): 256–61. doi:10.17305/bjbms.2010.2652. PMC 5627717. PMID 20433435.
  24. ^ Djukanovic L, et al. (2010). "Investigation of Balkan endemic nephropathy in Serbia: how to proceed?". Srp Arh Celok Lek. 138 (Suppl. 1): S68–72. doi:10.2298/SARH1004256D. PMID 20499513.
  25. ^ Castegnaro M, et al. (2006). "Balkan endemic nephropathy: role of ochratoxins A through biomarkers". Mol Nutr Food Res. 50 (6): 519–29. doi:10.1002/mnfr.200500182. PMID 16715544.
  26. ^ Long DT, Voice TC (2007). "Role of exposure analysis in solving the mystery of Balkan endemic nephropathy". Croat. Med. J. 48 (3): 300–11. PMC 2080532. PMID 17589972.
  27. ^ Abouzied MM, Horvath AD, Podlesny PM, et al. (2002). "Ochratoxin A concentrations in food and feed from a region with Balkan Endemic Nephropathy". Food Additives and Contaminants. 19 (8): 755–64. doi:10.1080/02652030210145036. PMID 12227939.
  28. ^ Fink-Gremmels J. (29 June – 1 July 2005). "Conclusions from the workshops on Ochratoxin A in Food: recent developments and significance". Organized by ILSI Europe in Baden (Austria).
  29. ^ Krogh P, et al. (1976). "Experimental porcine nephropathy: changes of renal function and structure peroraly induced by crystalline ochratoxin A". Acta Pathol Microbiol Scand A. 84 (5): 429–34. PMID 970130.
  30. ^ Hope JH, Hope BE (2012). "A Review of the Diagnosis and Treatment of Ochratoxin A Inhalational Exposure Associated with Human Illness and Kidney Disease including Focal Segmental Glomerulosclerosis". Journal of Environmental and Public Health. 2012: 1–10. doi:10.1155/2012/835059. PMC 3255309. PMID 22253638. Article ID 835059.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  31. ^ Niemiec, J.; Borzemska, W. (1994). "The effect of Ochratoxin A on egg quality development of embryos and the level of toxin in egg and tissue of hens and chicks". Journal of Animal and Feed Sciences. 3 (4): 309–316. doi:10.22358/jafs/69844/1994.
  32. ^ Battacone G. Nudda A. Pulina G. (2010). "Effects of Ochratoxin A on Livestock Production". Toxins. 2 (7): 1796–1824. doi:10.3390/toxins2071796. PMC 3153269. PMID 22069661.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  33. ^ Scientific Panel on Contaminants in the Food Chain (2006). "Opinion of the Scientific Panel on Contaminants in the Food Chain on a request from the Commission related to Ochratoxin A in Food, Question N° EFSA-Q-2005-154, Adopted on 4 April 2006". The EFSA Journal. 365: 1–56.
  34. ^ Codex Alimentarius Commission (1999). "Codex Committee on Food Additives and Contaminants, Position paper on ochratoxin A, Thirty-first Session, The Hague, The Netherlands, 22-26 March 1999" (PDF). Joint FAO/WHO Food Standards Programme: 1–9.
  35. ^ De Stefani; et al. (1998). "Meat intake, mate drinking and renal cell cancer in Uruguay: a case-control study". Br J Cancer. 78 (9): 1239–1243. doi:10.1038/bjc.1998.661. PMC 2062999. PMID 9820187.
  36. ^ Rashidkhani B, et al. (2005). "Major dietary patterns and risk of Renal Cell Carcinoma in a prospective cohort of Swedish women". J. Nutr. 135 (7): 1757–1762. doi:10.1093/jn/135.7.1757. PMID 15987861.
  37. ^ Boonen, Jente; Malysheva, Svetlana V.; Taevernier, Lien; Diana Di Mavungu, José; De Saeger, Sarah; De Spiegeleer, Bart (2012). "Human skin penetration of selected model mycotoxins". Toxicology. 301 (1–3): 21–32. doi:10.1016/j.tox.2012.06.012. PMID 22749975.
  38. ^ Woolf LI (1975). "Phenylketonuria as a balanced polymorphism: the nature of the heterozygote advantage". Annals of Human Genetics. 38: 461–469. doi:10.1111/j.1469-1809.1975.tb00635.x.
  39. ^ Withrock, Isabelle C.; Anderson, Stephen J.; Jefferson, Matthew A.; McCormack, Garrett R.; Mlynarczyk, Gregory S.A.; Nakama, Aron; Lange, Jennifer K.; Berg, Carrie A.; Acharya, Sreemoyee; Stock, Matthew L.; Lind, Melissa S.; Luna, K.C.; Kondru, Naveen C.; Manne, Sireesha; Patel, Bhavika B.; de la Rosa, Bierlein M.; Huang, Kuei-Pin; Sharma, Shaunik; Hu, Hilary Z.; Kanuri, Sri Harsha; Carlson, Steve A. (2015). "Genetic diseases conferring resistance to infectious diseases". Genes & Diseases. 2 (3): 247–254. doi:10.1016/j.gendis.2015.02.008. PMC 6150079. PMID 30258868.
  40. ^ "Ketosynthase domain probes identify two subclasses of fungal polyketide synthase genes". doi:10.1006. {{cite journal}}: Check |doi= value (help); Cite journal requires |journal= (help)
  41. ^ "A polyketide synthase gene required for ochratoxin A biosynthesis in Aspergillus ochraceus". doi:10.1099. {{cite journal}}: Check |doi= value (help); Cite journal requires |journal= (help)
  42. ^ "Design and utility of oligonucleotide gene probes for fungal polyketide synthases". doi:10.1016. {{cite journal}}: Check |doi= value (help); Cite journal requires |journal= (help)

Category:Mycotoxins Category:IARC Group 2B carcinogens Category:Isochromenes Category:Lactones Category:Phenols Category:Benzamides Category:Halogen-containing natural products Category:Chloroarenes Category:Suspected testicular toxins

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