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Papers by Carmen Méndez

Microbial Cell Factories, 2020

Background Mithramycin is an anti-tumor compound of the aureolic acid family produced by Streptom... more Background Mithramycin is an anti-tumor compound of the aureolic acid family produced by Streptomyces argillaceus. Its biosynthesis gene cluster has been cloned and characterized, and several new analogs with improved pharmacological properties have been generated through combinatorial biosynthesis. To further study these compounds as potential new anticancer drugs requires their production yields to be improved significantly. The biosynthesis of mithramycin proceeds through the formation of the key intermediate 4-demethyl-premithramycinone. Extensive studies have characterized the biosynthesis pathway from this intermediate to mithramycin. However, the biosynthesis pathway for 4-demethyl-premithramycinone remains unclear. Results Expression of cosmid cosAR7, containing a set of mithramycin biosynthesis genes, in Streptomyces albus resulted in the production of 4-demethyl-premithramycinone, delimiting genes required for its biosynthesis. Inactivation of mtmL, encoding an ATP-depende...

$Research paper thumbnail of {"__content__"=>"Characterization of the Jomthonic Acids Biosynthesis Pathway and Isolation of Novel Analogues in GUA-06-05-006A.", "i"=>{"__content__"=>"Streptomyces caniferus"}}$

Marine drugs, Jan 31, 2018

Jomthonic acids (JAs) are a group of natural products (NPs) with adipogenic activity. Structurall... more Jomthonic acids (JAs) are a group of natural products (NPs) with adipogenic activity. Structurally, JAs are formed by a modified β-methylphenylalanine residue, whose biosynthesis involves a methyltransferase that in has been identified as MppJ. Up to date, three JA members (A⁻C) and a few other natural products containing β-methylphenylalanine have been discovered from soil-derived microorganisms. Herein, we report the identification of a gene () coding for a putative methyltransferase highly identical to MppJ in the chromosome of the marine actinobacteria GUA-06-05-006A. In its 5' region, clusters with two polyketide synthases (PKS) (, ), a nonribosomal peptide synthetase (NRPS) () and a thioesterase gene (), possibly conforming a single transcriptional unit. Insertion of a strong constitutive promoter upstream of P1 led to the detection of JA A, along with at least two novel JA family members (D and E). Independent inactivation of , and abolished production of JA A, JA D and J...

Microbial Cell Factories, 2016

Natural Products: Discourse, Diversity, and Design, 2014

Molecular Microbiology, 2005

Microbial Biotechnology, 2012

Microbial Biotechnology, 2010

Metabolic Engineering, 2008

Production of secondary metabolites is a process influenced by several physico-chemical factors i... more Production of secondary metabolites is a process influenced by several physico-chemical factors including nutrient supply, oxygenation, temperature and pH. These factors have been traditionally controlled and optimized in industrial fermentations in order to enhance metabolite production. In addition, traditional mutagenesis programs have been used by the pharmaceutical industry for strain and production yield improvement. In the last years, the development of recombinant DNA technology has provided new tools for approaching yields improvement by means of genetic manipulation of biosynthetic pathways. These efforts are usually focused in redirecting precursor metabolic fluxes, deregulation of biosynthetic pathways and overexpression of specific enzymes involved in metabolic bottlenecks. In addition, efforts have been made for the heterologous expression of biosynthetic gene clusters in other organisms, looking not only for an increase of production levels but also to speed the process by using rapidly growing and easy to manipulate organisms compared to the producing organism. In this review, we will focus on these genetic approaches as applied to bioactive secondary metabolites produced by actinomycetes.

Journal of Natural Products, 2008

The Journal of Antibiotics, 2012

Gene, 1996

Mithramycin (Mtm) is an aromatic polyketide which shows antibacterial and antitumor activity. Fro... more Mithramycin (Mtm) is an aromatic polyketide which shows antibacterial and antitumor activity. From a chromosomal cosmid library of Streptomyces argillaceus, a Mtm producer, a clone (cosAR7) was isolated by homology to the actI/III region of S. coelicolor and the strDEM genes of S. griseus. From this clone, a 5.3-kb DNA region was sequenced and found to encode six open reading frames (designated as mtmQXPKST1), five of them transcribed in the same direction. The deduced products of five of these genes resembled components of type-II polyketide synthases. The mtm genes would code for an aromatase (mtmQ), a polypeptide of unknown function (mtmX), a beta-ketoacylsynthase (mtmP) and a related 'chain length factor' (mtmK), an acyl carrier protein (mtmS) and a beta-ketoreductase (mtmT1). The involvement of this gene cluster in Mtm biosynthesis was demonstrated by the Mtm non-producing phenotype of mutants generated in two independent insertional inactivation experiments.