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MetaCyc Pathway: actinorhodin biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis Antibiotic Biosynthesis

Some taxa known to possess this pathway include ? : Streptomyces coelicolor A3(2)

Expected Taxonomic Range: Actinobacteria

Summary:
General Background

The dimeric, benzoisochromanequinone antibiotic, actinorhodin, is an aromatic polyketide. Polyketides have been found to posses extensive biological activities and therefore, the actinorhodin pathway has undergone intensive genetic and biochemical studies for several years. The actinorhodin cluster is composed of 22 genes (SCO5071- SCO5092), which, in addition to the genes that encode catalytic enzymes, include genes that encode regulatory (SCO5082, SCO5085) and actinorhodin transport (SCO5083) proteins.

About This Pathway

Actinorhodin biosynthesis starts with 8 malonyl-CoAs and the minimal PKS, composed of a ketoacylsynthase, KSα, a chain-length factor, chain length factor, and an acyl carrier protein, actinorhodin polyketide synthase [acp]-like protein [McDaniel93]. The KSα and CLF form a heterodimer [FernandezMoreno92] and create a tunnel that stabilizes the growing polyketide backbone and controls chain length [Gualdi92][KeatingeClay04].

The first malonyl group is loaded onto the ACPPKS [Khosla92][Arthur06] by either the ACPPKS [Matharu98][Arthur05][Arthur06][Hitchman98] or a malonyltransferase from primary metabolism in a phenomenon termed 'cross talk' [Revill95][Khosla99] [Tang04][Carreras98]. Once loaded, it is decarboxylated to the starter acetyl group by the KSα [KeatingeClay04] and subsequently bound to KSα via a thioester bond. Once KSα is primed, a second malonyl group is transferred to ACPPKS and undergoes a KSα-catalyzed condensation with the acetyl starter group. 6 more malonyl groups are inidividually transferred to ACPPKS and condensed to the growing polyketide chain in the same manner [Sherman89][Bibb89][Meurer95][Arthur06]. The resultant chain is attached to the ACPPKS by a thioester bond.

As the chain grows into the KSα-CLF tunnel, it buckles, which is believed to initiate the first ring cyclization. Further molecular interactions complete formation of the first ring [KeatingeClay04].

Following first ring cyclization and with the carbon chain still attached to the ACPPKS, the C-9 keto-group is reduced to a hydroxyl group by ActIII [Hallam88][Bartel90] [Yu94][Teartasin04][Hadfield04][Sherman89][McDaniel93a][McDaniel93] [Fu94]. Subsequently, the first ring is aromatized by ActVII [McDaniel94] and then a second ring is formed by ActIV via an intramolecular aldol condensation [McDaniel94]. The compound is then released from ACPPKS as it was determined that a non-enzyme bound acid is the likely substrate for the next enzyme, ActVI-ORF1 [BookerMilburn05].

ActVI-ORF1 then reduces the keto-group at C-3 resulting in a chiral secondary alcohol [FernandezMoreno94] [Ichinose99][Taguchi00][Taguchi04]. A pyran ring is then formed with the assistance of ActVI-ORF3, followed by a spontaneous dehydration [FernandezMoreno94][Ichinose99] [Taguchi00]. The resulting compound, (S)-DNPA, was found to be the best trigger for actinorhodin export via a 'feed-forward' mechanism. (S)-DNPA, and to a lesser extent, actinorhodin itself, eliminates the interaction between the repressor, ActII-ORF1, and the operon, actII-ORF2-actII-ORF3 (SCO5083-SCO5084), allowing transcription of the operon. actII-ORF3 may encode an enzyme involved in the synthesis of a second actinorhodin pigment, γ-actinorhodin, while actII-ORF2 encodes the protein that exports both actinorhodins before their intracellular levels become toxic [Bystrykh96][Tahlan07].

In the next biosynthesis step, the double bond between C-14 and C-15 is reduced by ActVI-ORF2, while ActVI-ORF4 assists in formation of the chemically favored isomer [FernandezMoreno94] [Taguchi00]. ActVA-ORF6 then oxidizes the substrate to form a quinone [Sciara03][Kendrew00][Kendrew97], which is most likely dimerized at this point. Though this step has yet to be determined experimentally, basic chemistry favors dimerization before hydroxylation since the C-11 hydroxyl of the quinone substrate could easily direct coupling to the C-10 ortho position [Kendrew95].

Finally, the actinorhodin precursor is oxidized by a two-component NADH:flavin-dependent monooxygenase system, composed of ActVII and ActVA-ORF5. ActVB is the NADH:flavin reductase which reduces FMN in the presence of cofactor, NADH. ActVA-ORF5 then binds the reduced FMN along with molecular oxygen, forming an electrophillic flavin hydroperoxide intermediate. This intermediate then oxidizes the actinorhodin precursor, subsequently releasing an oxidized FMN which diffuses from ActVA-ORF5 to ActVB for another cycle [Valton06][Filisetti05][Valton04][Filisetti03][Kendrew95][Cole87].

Citations: [Shen93, Aceti98, Rudd79, He00, Wietzorrek97, Fu94a, Parro91, Leavitt94, Kang97, Sherman92, Taguchi07, Kim95c, Hillen82, Arias99, Bisang99, Crump96, FernandezMoreno91, Gramajo93, Ichinose98, Fu94b, Hopwood04, Caballero91, Omura86, McDaniel94a, Caballero91a, Tang03, Crump97, Malpartida, Malpartida86, Hopwood, Zhang90, Hesketh03, Kanehisa05, Kanehisa05a, Ichinose01, Hopwood07, Summers95]

Credits:
Created 22-Jan-2007 by Armendarez V , JIC


References

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Ichinose01: Ichinose K, Taguchi T, Bedford DJ, Ebizuka Y, Hopwood DA (2001). "Functional complementation of pyran ring formation in actinorhodin biosynthesis in Streptomyces coelicolor A3(2) by ketoreductase genes for granaticin biosynthesis." J Bacteriol 183(10);3247-50. PMID: 11325954

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Kanehisa05a: Kanehisa Laboratories (2005). "Biosynthesis of Type II Polyketide Products." KEGG: Kyoto Encyclopedia of Genes and Genomes. PMID: 16381885

Kang97: Kang JG, Hahn MY, Ishihama A, Roe JH (1997). "Identification of sigma factors for growth phase-related promoter selectivity of RNA polymerases from Streptomyces coelicolor A3(2)." Nucleic Acids Res 25(13);2566-73. PMID: 9185565

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Kendrew00: Kendrew SG, Federici L, Savino C, Miele A, Marsh EN, Vallone B (2000). "Crystallization and preliminary X-ray diffraction studies of a monooxygenase from Streptomyces coelicolor A3(2) involved in the biosynthesis of the polyketide actinorhodin." Acta Crystallogr D Biol Crystallogr 56(Pt 4);481-3. PMID: 10739927

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McDaniel94: McDaniel, R., Ebert-Khosla, S., Hopwood, D.A., Khosla, C. (1994). "Engineered Biosynthesis of Novel Polyketides: actVII and actIV Genes Encode Aromatase and Cyclase Enzymes, Respectively." J. Am. Chem. Soc. 116(24): 10855-10859.

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Teartasin04: Teartasin W, Limpkin C, Glod F, Spencer J, Cox RJ, Simpson TJ, Crosby J, Crump MP, Hadfield AT (2004). "Expression, purification and preliminary X-ray diffraction analysis of a ketoreductase from a type II polyketide synthase." Acta Crystallogr D Biol Crystallogr 60(Pt 6);1137-8. PMID: 15159580

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Valton06: Valton J, Fontecave M, Douki T, Kendrew SG, Niviere V (2006). "An aromatic hydroxylation reaction catalyzed by a two-component FMN-dependent Monooxygenase. The ActVA-ActVB system from Streptomyces coelicolor." J Biol Chem 281(1);27-35. PMID: 16267053

Wietzorrek97: Wietzorrek A, Bibb M (1997). "A novel family of proteins that regulates antibiotic production in streptomycetes appears to contain an OmpR-like DNA-binding fold." Mol Microbiol 25(6);1181-4. PMID: 9350875

Yu94: Yu TW, Bibb MJ, Revill WP, Hopwood DA (1994). "Cloning, sequencing, and analysis of the griseusin polyketide synthase gene cluster from Streptomyces griseus." J Bacteriol 176(9);2627-34. PMID: 8169211

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Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Byers07: Byers DM, Gong H (2007). "Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family." Biochem Cell Biol 85(6);649-62. PMID: 18059524

CambridgeSoft06: CambridgeSoft (2006). "ChemDraw Ultra 10.0." ChemDraw, Level Ultra, Version 10.0.

Huang92: Huang CJ, Fwu ML (1992). "Protein insufficiency aggravates the enhanced lipid peroxidation and reduced activities of antioxidative enzymes in rats fed diets high in polyunsaturated fat." J Nutr 122(5);1182-9. PMID: 1564572

Kim94: Kim ES, Hopwood DA, Sherman DH (1994). "Analysis of type II polyketide beta-ketoacyl synthase specificity in Streptomyces coelicolor A3(2) by trans complementation of actinorhodin synthase mutants." J Bacteriol 176(6);1801-4. PMID: 8132481

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Rubio06: Rubio S, Larson TR, Gonzalez-Guzman M, Alejandro S, Graham IA, Serrano R, Rodriguez PL (2006). "An Arabidopsis mutant impaired in coenzyme A biosynthesis is sugar dependent for seedling establishment." Plant Physiol 140(3);830-43. PMID: 16415216

Smith92a: Smith RC, McCarthy S (1992). "Physics of magnetic resonance." J Reprod Med 37(1);19-26. PMID: 1548634

Tattam: Tattam A "No nurses necessary." Nurs Times 86(34);18. PMID: 2395677


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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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