The biosynthesis of 4-hydroxycoumarin and dicoumarol by <i>Aspergillus fumigatus</i> Fresenius

Bye, Ann; King, Hugh K.

doi:10.1042/bj1170237

Cited by 48 publications

(21 citation statements)

References 11 publications

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“…Coumarin itself was not found to be 4-hydroxylated by fungi. Trans-2-coumaric acid is hydrated to give 3-hydroxymelilotic acid which then undergoes dehydrogenation to yield 3-oxomelilotic acid (Bye and King 1970). These acids are present as their CoA thioesters.…”

Section: Introductionmentioning

confidence: 99%

A novel 4-hydroxycoumarin biosynthetic pathway

et al. 2009

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Coumarin forms in melilotoside (trans-ortho-coumaric acid glucoside)-containing plant species upon cell damage. In moldy melilotoside-containing plant material, trans-ortho-coumaric acid is converted by fungi to 4-hydroxycoumarin, two molecules of which spontaneously combine with formaldehyde to give dicoumarol. Dicoumarol causes internal bleeding in livestock and is the forerunner of the warfarin group of medicinal anticoagulants. Here, we report 4-hydroxycoumarin formation by biphenyl synthase (BIS). Two new BIS cDNAs were isolated from elicitor-treated Sorbus aucuparia cell cultures. The encoded isoenzymes preferred ortho-hydroxybenzoyl (salicoyl)-CoA as a starter substrate and catalyzed a single decarboxylative condensation with malonyl-CoA to give 4-hydroxycoumarin. When elicitor-treated S. aucuparia cell cultures were fed with the N-acetylcysteamine thioester of salicylic acid, 4-hydroxycoumarin accumulated in the culture medium. Incubation of the BIS isoenzymes with benzoyl-CoA and malonyl-CoA resulted in the formation of 3,5-dihydroxybiphenyl which is the precursor of the phytoalexins of the Maloideae.

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Section: Introductionmentioning

confidence: 99%

A novel 4-hydroxycoumarin biosynthetic pathway

et al. 2009

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“…It has also been used in the treatment of lymphedema [4]. It also exhibits anticoagulant property when converted to dicoumarin by the strain of fungi Aspergillus fumigatus [5]. Further, it inhibits the release of plasma clotting factor VII by vitamin K without inhibition of protein synthesis [6].…”

Section: Introductionmentioning

confidence: 99%

Elucidation of the Binding Mechanism of Coumarin Derivatives with Human Serum Albumin

et al. 2013

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Coumarin is a benzopyrone which is widely used as an anti-coagulant, anti-oxidant, anti-cancer and also to cure arthritis, herpes, asthma and inflammation. Here, we studied the binding of synthesized coumarin derivatives with human serum albumin (HSA) at physiological pH 7.2 by using fluorescence spectroscopy, circular dichroism spectroscopy, molecular docking and molecular dynamics simulation studies. By addition of coumarin derivatives to HSA the maximum fluorescence intensity was reduced due to quenching of intrinsic fluorescence upon binding of coumarin derivatives to HSA. The binding constant and free energy were found to be 1.957±0.01×105 M−1, −7.175 Kcal M−1 for coumarin derivative (CD) enamide; 0.837±0.01×105 M−1, −6.685 Kcal M−1 for coumarin derivative (CD) enoate, and 0.606±0.01×105 M−1, −6.49 Kcal M−1 for coumarin derivative methylprop (CDM) enamide. The CD spectroscopy showed that the protein secondary structure was partially unfolded upon binding of coumarin derivatives. Further, the molecular docking studies showed that coumarin derivatives were binding to HSA at sub-domain IB with the hydrophobic interactions and also with hydrogen bond interactions. Additionally, the molecular dynamics simulations studies contributed in understanding the stability of protein-drug complex system in the aqueous solution and the conformational changes in HSA upon binding of coumarin derivatives. This study will provide insights into designing of the new inspired coumarin derivatives as therapeutic agents against many life threatening diseases.

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“…Se ha descrito que las cumarinas tienen como órganos blanco para su toxicidad y carcinogenicidad a hígado y pulmón en ratón y rata (Lake, 1999). También se han relacionado con afectación a la síntesis de los factores de coagulación en el hígado, además de ser causantes de hemorragias (Bye & King, 1970, Pineda-Ruiz, 2009). Por lo que la presencia de cumarinas y otros compuestos aislados de R. graveolens podrían estar induciendo un efecto tóxico en los hepatocitos, congestión vascular, e infiltrados de células mononucleares observados en los grupos expuestos a distintas concentraciones del extracto de R. graveolens.…”

Section: Discussionunclassified

Efecto Tóxico del Extracto Acuoso de Ruta graveolens del Norte de México sobre el Hígado de Rata Wistar

et al. 2013

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RESUMEN:A Ruta graveolens se le atribuyen propiedades benéficas en medicina tradicional, sin embargo se ha demostrado que también puede producir efectos adversos. A la fecha no existe evidencia que ratifique que R. graveolens es totalmente inofensiva, por este motivo el objetivo de este estudio fue determinar el efecto tóxico del extracto acuoso de las hojas de esta especie vegetal en hígado de rata. Se utilizaron 25 ratas Wistar y se dividieron en 5 grupos (n=5). El grupo 1 correspondió al grupo control negativo, el grupo 2 o control positivo se trató con 100 mg de dexametasona/kg/día. Los grupos 3 y 4 se trataron con 30 y 100 mg de extracto de R. graveolens respectivamente. Al grupo 5 se le administraron 100 mg de dexametasona/kg/día combinado con 100 mg de extracto de R. graveolens/ kg/día. Las administraciones se realizaron vía intraperitoneal por tres días. Los animales se sacrificaron por dislocación cervical. Las muestras de hígado se fijaron en formalina y posteriormente se incluyeron en parafina. Se obtuvieron cortes histológicos de 5 micras de grosor que se tiñeron con Hematoxilina-Eosina para la evaluación histológica con microscopia de luz. Los resultados demuestran por primera vez que la exposición al extracto acuoso de R. graveolens induce alteraciones morfológicas en el hígado de ratas Wistar. Estas alteraciones se observaron de manera leve en el grupo 3 y se incrementaron en el grupo 4. Destacó que el mayor daño se observó en el grupo 5. Se concluye que el extracto acuoso de R. graveolens resultó tóxico, sin embargo es necesario realizar estudios adicionales con el fin de caracterizar otros efectos toxicológicos que soporten el riesgo del uso de R. graveolens en medicina tradicional a largo plazo.

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The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius

Cited by 48 publications

References 11 publications

A novel 4-hydroxycoumarin biosynthetic pathway

A novel 4-hydroxycoumarin biosynthetic pathway

Elucidation of the Binding Mechanism of Coumarin Derivatives with Human Serum Albumin

Efecto Tóxico del Extracto Acuoso de Ruta graveolens del Norte de México sobre el Hígado de Rata Wistar

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