Triumphs and Challenges of Natural Product Discovery in the Postgenomic Era.

Natural products have played significant roles as medicine and food throughout human history. Here, we first provide a brief historical overview of natural products, their classification, biosynthetic origins, and the microbiological and genetic methods used for their discovery. We also describe and discuss the technologies that revolutionized the field, which transitioned from classic genetics to genome-centric discovery approximately two decades ago. We then highlight the most recent advancements and approaches in the current postgenomic era, in which genome mining is a standard operation and high-throughput analytical methods allow parallel discovery of genes and molecules at an unprecedented pace. Finally, we discuss the new challenges faced by the field of natural products and the future of systematic heterologous expression and strain-independent discovery, which promises to deliver more molecules in vials than ever before.

Spatial ecology and conservation of leatherback turtles (Dermochelys coriacea) nesting in Bioko, Equatorial Guinea.

Bioko Island (Equatorial Guinea) hosts important nesting habitat for leatherback sea turtles, with the main nesting beaches found on the island's southern end. Nest monitoring and protection have been ongoing for more than two decades, although distribution and habitat range at sea remains to be determined. This study uses satellite telemetry to describe the movements of female leatherback turtles (n = 10) during and following the breeding season, tracking them to presumed offshore foraging habitats in the south Atlantic Ocean. Leatherback turtles spent 100% of their time during the breeding period within the Exclusive Economic Zone (EEZ) of Equatorial Guinea, with a core distribution focused on the south of Bioko Island extending up to 10 km from the coast. During this period, turtles spent less than 10% of time within the existing protected area. Extending the border of this area by 3 km offshore would lead to a greater than threefold increase in coverage of turtle distribution (29.8 ± 19.0% of time), while an expansion to 15 km offshore would provide spatial coverage for more than 50% of tracking time. Post-nesting movements traversed the territorial waters of Sao Tome and Principe (6.4%of tracking time), Brazil (0.85%), Ascension (1.8%), and Saint Helena (0.75%). The majority (70%) of tracking time was spent in areas beyond national jurisdiction (i.e. the High Seas). This study reveals that conservation benefits could be achieved by expanding existing protected areas stretching from the Bioko coastal zone, and suggests shared migratory routes and foraging space between the Bioko population and other leatherback turtle rookeries in this region.

Late Systemic Lupus Erythematosus-Associated Insulin Resistance Syndrome: A Rare Cause of De Novo Diabetes Mellitus.

The association of type B insulin resistance syndrome (TBIRS) due to autoimmune diseases such as systemic lupus erythematosus (SLE) is uncommon. This is partly due to the lack of established criteria for the diagnosis of this resistance. However, some clinical aspects may suggest that the diagnosis does not necessarily have to be positive insulin receptor antibodies as such patients could respond to immunosuppressive treatment. Methods. We describe a case and have performed a literature review on PubMed/MEDLINE, EMBASE, and Google Scholar bibliographic databases to identify all case reports. All available studies from January 1975 through December 2020 were included. Data collected were tabulated, and outcomes were analyzed cumulatively. Results. Thirty-one cases of TBIRS associated with SLE have been described. These patients presented with catabolic symptoms and hyperglycemia in most cases, with an average time from the onset of symptoms of four months. In addition to that clinical characteristics related to SLE were variable, along with certain common characteristics such as acanthosis in 60% of patients. Almost all the patients had antibodies against insulin receptors. The insulin doses required by the patients ranged from 450 to 25,000 U daily. Remission was achieved in 80% of the patients with a two-year follow-up. Most patients associated with late-onset SLE, like our patient, achieved metabolic control after immunosuppressive treatment. Conclusion. High insulin resistance in patients with de novo diabetes mellitus (DM) without obesity should be considered as a possible clinical manifestation of an autoimmune disease such as SLE, with a good metabolic response to the immunosuppressive management established.

Mutación heterocigota, autosómica recesiva del gen RARS2 en una paciente colombiana de padres no consanguíneos / Autosomal recessive heterocygote mutation of the RARS2 gene in a colombian patient with non- consanguineous parents

Las nuevas metodologías de secuenciación masiva han permitido caracterizar e identificar variantes genéticas asociadas a diferentes patologías. En este trabajo se presenta el caso de una paciente con una mutación del gen RARS2 que codifica la enzima arginino-ARNt ligasa para la codificación de proteínas. Esta alteración genética se manifiesta en hipoplasia pontocerebelosa tipo 6, con una prevalencia de <1/1 000 0000, caracterizada por un cerebelo y un puente de menor tamaño asociados a un retraso grave en el neurodesarrollo. El análisis de caso permite un mejor conocimiento de enfermedades de origen genético, específicamente, de aquellas con patrones de herencia autosómicos recesivos de padres no consanguíneos. Su estudio sobre todo en lo relacionado con el ámbito familiar y socioeconómico, y su base genética, ayuda a una mejor calidad de vida de los pacientes y su familia.

The latest method of next-generation sequencing has allowed the characterization and identification of genetic variants associated to diverse pathologies. In this article, we present the case of female patient with a mutation of the RARS2 gene that encodes the enzyme for arginyl tRNA synthetase for coding of proteins. This genetic alteration manifests in pontocerebellar hypoplasia type 6, with a prevalence of <1/1,000,0000, characterized by a cerebellum and pons that are smaller in size and are associated with severe neurodevelopmental delay. The analysis of the case of this patient provides better knowledge of diseases of genetic origin; specifically, regarding genetic diseases of autosomal recessive patterns of inheritance from non-consanguineous parents. The impact of these studies; specially within the family, social, economic and genetic aspects helps provide a better quality of life for these patients and their family.

[Autosomal recessive heterocygote mutation of the RARS2 gene in a colombian patient with non- consanguineous parents]. / Mutación heterocigota, autosómica recesiva del gen RARS2 en una paciente colombiana de padres no consanguíneos.

The latest method of next-generation sequencing has allowed the characterization and identification of genetic variants associated to diverse pathologies. In this article, we present the case of female patient with a mutation of the RARS2 gene that encodes the enzyme for arginyl tRNA synthetase for coding of proteins. This genetic alteration manifests in pontocerebellar hypoplasia type 6, with a prevalence of<1/1,000,0000, characterized by a cerebellum and pons that are smaller in size and are associated with severe neurodevelopmental delay. The analysis of the case of this patient provides better knowledge of diseases of genetic origin; specifically, regarding genetic diseases of autosomal recessive patterns of inheritance from non-consanguineous parents. The impact of these studies; specially within the family, social, economic and genetic aspects helps provide a better quality of life for these patients and their family.

Las nuevas metodologías de secuenciación masiva han permitido caracterizar e identificar variantes genéticas asociadas a diferentes patologías. En este trabajo se presenta el caso de una paciente con una mutación del gen RARS2 que codifica la enzima arginino-ARNt ligasa para la codificación de proteínas. Esta alteración genética se manifiesta en hipoplasia pontocerebelosa tipo 6, con una prevalencia de<1/1 000 0000, caracterizada por un cerebelo y un puente de menor tamaño asociados a un retraso grave en el neurodesarrollo. El análisis de caso permite un mejor conocimiento de enfermedades de origen genético, específicamente, de aquellas con patrones de herencia autosómicos recesivos de padres no consanguíneos. Su estudio sobre todo en lo relacionado con el ámbito familiar y socioeconómico, y su base genética, ayuda a una mejor calidad de vida de los pacientes y su familia.

New insights into the taxonomy of autoimmune diseases based on polyautoimmunity.

OBJECTIVE: The clinical coexistence of two or more autoimmune diseases (ADs) fulfilling classification criteria is termed "overt polyautoimmunity" (PolyA), whereas the presence of autoantibodies unrelated to an index AD, without clinical criteria fulfillment, is known as "latent PolyA". We aimed to explore a new taxonomy of ADs based on PolyA. METHODS: In a cross-sectional study of 292 subjects, we evaluated the presence of PolyA in 146, 45, 29, 17, and 17 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), autoimmune thyroid disease (AITD) and systemic sclerosis (SSc), respectively, and 38 healthy controls. Clinical assessment, autoantibody profile (by autoantigen array chip), lymphocytes immunophenotype and cytokine profile (by flow cytometry) were evaluated simultaneously. A mixed cluster methodology was used to classify ADs. RESULTS: Latent PolyA was more frequent than overt PolyA, ranging from 69.9% in RA to 100% in SSc. Nevertheless, both latent and overt PolyA clustered together. Over-expressed IgG autoantibodies were found to be hallmarks for the identification of index ADs. The combination of autoantibodies allowed high accuracy in the classification of ADs. Three well-defined clusters based on PolyA were observed with distinctive clinical and immunological phenotypes. CONCLUSIONS: This proof-of-concept study indicates that ADs can be classified according to PolyA. PolyA should be considered in all studies dealing with ADs, including epidemiological, genetic, and clinical trials.

The Surfactin-Like Lipopeptides From Bacillus spp.: Natural Biodiversity and Synthetic Biology for a Broader Application Range.

Surfactin is a lipoheptapeptide produced by several Bacillus species and identified for the first time in 1969. At first, the biosynthesis of this remarkable biosurfactant was described in this review. The peptide moiety of the surfactin is synthesized using huge multienzymatic proteins called NonRibosomal Peptide Synthetases. This mechanism is responsible for the peptide biodiversity of the members of the surfactin family. In addition, on the fatty acid side, fifteen different isoforms (from C12 to C17) can be incorporated so increasing the number of the surfactin-like biomolecules. The review also highlights the last development in metabolic modeling and engineering and in synthetic biology to direct surfactin biosynthesis but also to generate novel derivatives. This large set of different biomolecules leads to a broad spectrum of physico-chemical properties and biological activities. The last parts of the review summarized the numerous studies related to the production processes optimization as well as the approaches developed to increase the surfactin productivity of Bacillus cells taking into account the different steps of its biosynthesis from gene transcription to surfactin degradation in the culture medium.

EMA Review of Belantamab Mafodotin (Blenrep) for the Treatment of Adult Patients with Relapsed/Refractory Multiple Myeloma.

On August 25, 2020, a marketing authorization valid through the European Union was issued for belantamab mafodotin monotherapy for the treatment of multiple myeloma (MM) in adult patients who have received at least four prior therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy. Belantamab mafodotin is an antibody-drug conjugate that combines a mAb, which binds specifically to B-cell maturation antigen, with maleimidocaproyl monomethyl auristatin F, which is a cytotoxic agent. It was evaluated in Study 205678 (DREAMM-2), an open-label, two arm, phase II, multicenter study in patients with MM who had relapsed following treatment with at least three prior therapies, who were refractory to an IMiD, a PI, and an anti-CD38 mAb alone or in combination. Patients were randomized to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) belantamab mafodotin by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Belantamab mafodotin achieved an overall response rate (ORR) of 32% (97.5% confidence interval [CI]: 22-44) with a median duration of response (DoR) of 11 months (95% CI: 4.2 to not reached). The most frequently (≥20%) reported adverse reactions grades 3-4 with belantamab mafodotin were keratopathy (31%), thrombocytopenia (22%), and anemia (21%). With regard to the corneal risks associated with belantamab mafodotin, patients would need to undergo specific ophthalmic examinations so that any findings can be promptly and adequately managed. The scientific review concluded that a 32% ORR and a median DoR of 11 months observed with belantamab mafodotin was considered clinically meaningful. Given the manageable toxicity profile and considering that belantamab mafodotin has a mechanism of action that is different from that of authorized treatments in this group of highly pretreated patients whose disease is refractory to three classes of agents, the benefit risk for belantamab mafodotin monotherapy was considered positive, although the efficacy and safety evidence were not as comprehensive as normally required. IMPLICATIONS FOR PRACTICE: Belantamab mafodotin (Blenrep, GlaxoSmithKline, St. Louis, MO, U.S.A) was approved in the European Union as monotherapy for the treatment of adult patients with refractory/relapsed multiple myeloma. Belantamab mafodotin resulted in durable response in highly pretreated patients whose disease is refractory to three classes of agents. Belantamab mafodotin is a monoclonal antibody against B-cell maturation antigen conjugated with the potent antimitotic agent maleimidocaproyl monomethyl auristatin. This is the first monoclonal antibody to target this antigen in multiple myeloma, which represents a true novelty from a pharmacological point of view.

Discovery of Thanafactin A, a Linear, Proline-Containing Octalipopeptide from Pseudomonas sp. SH-C52, Motivated by Genome Mining.

Genome mining of the bacterial strains Pseudomonas sp. SH-C52 and Pseudomonas fluorescens DSM 11579 showed that both strains contained a highly similar gene cluster encoding an octamodular nonribosomal peptide synthetase (NRPS) system which was not associated with a known secondary metabolite. Insertional mutagenesis of an NRPS component followed by comparative profiling led to the discovery of the corresponding novel linear octalipopeptide thanafactin A, which was subsequently isolated and its structure determined by two-dimensional NMR and further spectroscopic and chromatographic methods. In bioassays, thanafactin A exhibited weak protease inhibitory activity and was found to modulate swarming motility in a strain-specific manner.

Progressive Early-Onset Leukodystrophy Related to Biallelic Variants in the KARS Gene: The First Case Described in Latin America.

The KARS gene encodes the aminoacyl-tRNA synthetase (aaRS), which activates and joins the lysin with its corresponding transfer RNA (tRNA) through the ATP-dependent aminoacylation of the amino acid. KARS gene mutations have been linked to diverse neurologic phenotypes, such as neurosensorial hearing loss, leukodystrophy, microcephaly, developmental delay or regression, peripheral neuropathy, cardiomyopathy, the impairment of the mitochondrial respiratory chain, and hyperlactatemia, among others. This article presents the case of a Colombian pediatric patient with two pathological missense variants in a compound heterozygous state in the KARS gene and, in addition to the case report, the paper reviews the literature for other cases of KARS1-associated leukodystrophy.

Draft Genome Sequence of Ochrobactrum sp. Strain MC-1LL, a Bacterial Strain with Antimicrobial Properties, Isolated from Marine Sediments in Nigeria.

Here, we report a 4.3-Mb draft genome sequence of a potential new Ochrobactrum species, which clarified its taxonomic position and gave insight into the complete secondary metabolite production capacity of the strain.

Draft Genome Sequence of Lipopeptide-Producing Strain Pseudomonas fluorescens DSM 11579 and Comparative Genomics with Pseudomonas sp. Strain SH-C52, a Closely Related Lipopeptide-Producing Strain.

Pseudomonas fluorescens DSM 11579 is known to be a producer of the lipopeptides brabantamide and thanamycin. Its draft genome gives insight into the complete secondary metabolite production capacity of the strain and builds the basis for a comparative study with Pseudomonas sp. strain SH-C52, a lipopeptide-producing strain involved in natural disease-suppressive soils.

Computer-aided re-engineering of nonribosomal peptide and polyketide biosynthetic assembly lines.

Covering: 2014 to 2019Nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) have been the subject of engineering efforts for multiple decades. Their modular assembly line architecture potentially allows unlocking vast chemical space for biosynthesis. However, attempts thus far are often met with mixed success, due to limited molecular compatibility of the parts used for engineering. Now, new engineering strategies, increases in genomic data, and improved computational tools provide more opportunities for major progress. In this review we highlight some of the challenges and progressive strategies for the re-design of NRPSs & type I PKSs and survey useful computational tools and approaches to attain the ultimate goal of semi-automated and design-based engineering of novel peptide and polyketide products.

Draft Genome Sequence of the Novonestmycin-Producing Strain Streptomyces sp. Z26, Isolated from Potato Rhizosphere in Morocco.

Streptomyces sp. strain Z26 exhibited antifungal activity and turned out to be a producer of the secondary metabolites novonestmycin A and B. The 6.5-Mb draft genome gives insight into the complete secondary metabolite production capacity and builds the basis to find and locate the biosynthetic gene cluster encoding the novonestmycins.

Late diagnosis of pseudohypoparathyroidism in adulthood. Case series / Pseudohipoparatiroidismo diagnosticado tardíamente en la adultez, una serie de casos

Abstract Introduction: Pseudohypoparathyroidism (PHP) is a rare hereditary disease, characterized by hypocalcemia/hyperphosphatemia secondary to peripheral resistance to parathyroid hormone (PTH). PHP diagnosis is usually precluded since hypocalcemia is considered as the primary diagnosis, thus delaying further diagnostic studies and preventing an adequate management of this clinical condition. Materials and methods: Retrospective review of the databases of the Endocrinology departments of two tertiary care centers of Medellin, Colombia from January 2012 to December 2016. Patients diagnosed with PHP based on clinical presentation and confirmatory laboratory values were included. Results: Four patients met the inclusion criteria. All PHP cases were diagnosed in adulthood despite strong early clinical and laboratory evidence of the disease. Three patients were diagnosed with Fahr's syndrome and two with Albright's hereditary osteodystrophy. The mean values obtained were PTH of 376.8 pg/mL, calcium of 6.17 mg/dL and phosphorus of 6.55 mg/dL. Conclusions: PHP is a rare disorder. This paper describes four PHP cases diagnosed during adulthood. Emphasis should be placed on the judicious approach to the patient with hypocalcemia and hyperphosphatemia with increased PTH and normal renal function, since these symptoms strongly suggest a diagnosis of PHP.

Resumen Introducción. El pseudohipoparatiroidismo (PHP) es una condición rara caracterizada por hipocalcemia e hiperfosfatemia secundarias a resistencia periférica a la hormona paratiroidea (PTH). Es frecuente que la hipocalcemia sea establecida de forma equivocada como diagnóstico primario y que el diagnóstico definitivo de PHP sea tardío, difiriendo los estudios y el manejo específico que exigen estos pacientes. Materiales y métodos. Se revisaron de forma retrospectiva las bases de datos de endocrinología de dos centros terciarios de Medellín, Colombia, desde enero de 2012 a diciembre de 2016. Se incluyeron pacientes con diagnóstico de PHP por presentación clínica y valores confirmatorios de laboratorio. Resultados. Cuatro pacientes cumplieron los criterios de inclusión. Todos los casos fueron diagnosticados en la adultez a pesar de tener evidencia temprana, clínica y bioquímica de la enfermedad. Tres pacientes tenían síndrome de Fahr y dos tenían osteodistrofia hereditaria de Albright. Los valores medios registrados fueron PTH de 376.8 pg/mL, calcio de 6.17 mg/dL y fósforo de 6.55 mg/dL. Conclusiones. El PHP es un trastorno raro; se describen cuatro casos diagnosticados de forma tardía en la adultez. Se enfatiza en el enfoque juicioso del paciente con hipocalcemia, la cual, en presencia de hiperfosfatemia con PTH elevada y función renal normal, debe hacer sospechar el diagnóstico de PHP.

Resultados del tratamiento multidisciplinario de tumores neuroendocrinos de intestino delgado / Outcomes of multidisciplinary treatment of neuroendocrine tumors of the small intestine

Resumen Objetivos: Describir los resultados del tratamiento de pacientes con tumores neuroendocrinos (TNE) del intestino delgado tratados por un grupo multidisciplinario. Métodos: Estudio tipo serie de casos en pacientes con diagnóstico histológico confirmado de tumor neuroendocrino con primario intestinal entre el 1 de mayo de 2004 y el 30 de abril de 2014. Resultados: En el periodo del estudio se atendieron en la institución 301 pacientes con diagnóstico de TNE de diferentes localizaciones, de los cuales 48 casos de primario intestinal reunieron los criterios de inclusión. La cirugía con intención curativa o paliativa fue la primera línea de tratamiento en la mayoría de pacientes (n = 35; 72,9%) y se logró remisión completa en 13 de ellos. Los análogos de somatostatina fueron la primera línea de manejo en el 14,5%. Al momento de la última valoración: 13 pacientes (27,1%) estaban libres de enfermedad; 17 pacientes (35,4%) se encontraban estables, y 7 pacientes (14,6%) con enfermedad en progresión. Más del 50% de los pacientes permanecieron vivos a los 5 años luego del diagnóstico. La mayor edad al momento del diagnóstico, la presencia de síndrome carcinoide, el compromiso metastásico, el grado histológico, y los valores elevados de marcadores bioquímicos (cromogranina A y 5-hidróxi indol ácido acético), fueron factores que se encontraron asociados a un peor pronóstico de supervivencia. Conclusiones: En el presente artículo se resumen los resultados clínicos del tratamiento de los pacientes con TNE de primario intestinal en un grupo multidisciplinario y la confrontación de dichos resultados con los datos disponibles en la literatura.

Abstract Aim: To describe the outcomes in a group of patients with neuroendocrine tumors (NETs) of the small intestine treated in a multidisciplinary group. Methods: A descriptive study based on the clinical records of patients with confirmed histological diagnosis of a neuroendocrine tumor with intestinal primary between 1 May 2004 and 30 April 2014 Results: A total of 301 patients diagnosed with NETs in different locations were treated during the study period, of which 48 cases of intestinal primary met the inclusion criteria. Surgery with curative or palliative intent was the first line of treatment in most patients (n = 35, 72.9%) and complete remission was achieved in 13 of them. Somatostatin analogues were the first line of management in 14.5%. At the time of the last assessment, 13 patients (27.1%) remained disease-free, 17 patients (35.4%) with persistent but stable disease, and 7 patients (14.6%) had progressive disease. More than 50% of the patients remained alive at 55 months after diagnosis. The higher age at diagnosis, the presence of carcinoid syndrome, the metastatic compromise, the histological grade, and elevated biochemical markers (Chromogranin A and 5-hydroxy indole acetic acid) were factors associated with a worse survival prognosis. Conclusions: A summary is presented on the clinical outcomes of the treatment of patients with NET of primary intestinal by a multidisciplinary group, as well as the comparison of these outcomes with the data available in the literature.

Caboxamycin biosynthesis pathway and identification of novel benzoxazoles produced by cross-talk in Streptomyces sp. NTK 937.

Streptomyces sp. NTK937, producer of benzoxazole antibiotic caboxamycin, produces in addition a methyl ester derivative, O-methylcaboxamycin. Caboxamycin cluster, comprising one regulatory and nine structural genes, has been delimited, and each gene has been individually inactivated to demonstrate its role in the biosynthetic process. The O-methyltransferase potentially responsible for O-methylcaboxamycin synthesis would reside outside this cluster. Five of the genes, cbxR, cbxA, cbxB, cbxD and cbxE, encoding a SARP transcriptional regulator, salicylate synthase, 3-oxoacyl-ACP-synthase, ACP and amidohydrolase, respectively, have been found to be essential for caboxamycin biosynthesis. The remaining five structural genes were found to have paralogues distributed throughout the genome, capable of partaking in the process when their cluster homologue is inactivated. Two of such paralogues, cbxC' and cbxI', coding an AMP-dependent synthetase-ligase and an anthranilate synthase, respectively, have been identified. However, the other three genes might simultaneously have more than one paralogue, given that cbxF (DAHP synthase), cbxG (2,3-dihydro-2,3-dihydroxybenzoate dehydrogenase) and cbxH (isochorismatase) have three, three and five putative paralogue genes, respectively, of similar function within the genome. As a result of genetic manipulation, a novel benzoxazole (3'-hydroxycaboxamycin) has been identified in the salicylate synthase-deficient mutant strain ΔcbxA. 3'-hydroxycaboxamycin derives from the cross-talk between the caboxamycin and enterobactin pathways.

Crosstalk of Nataxazole Pathway with Chorismate-Derived Ionophore Biosynthesis Pathways in Streptomyces sp. Tü 6176.

Streptomyces sp. Tü 6176, producer of cytotoxic benzoxazoles AJI9561, nataxazole, and 5-hydroxy-nataxazole, has been found to produce a fourth benzoxazole, UK-1. All derive from 3-hydroxy-anthranilate synthesized by the nataxazole biosynthesis machinery. However, biosynthesis of AJI9561, nataxazole, and 5-hydroxy-nataxazole requires 6-methylsalicylic acid also provided by nataxazole biosynthesis pathway, while biosynthesis of UK-1 utilizes salicylic acid produced by a salicylate synthase from the coelibactin biosynthesis pathway. This clearly suggests crosstalk between nataxazole and coelibactin pathways. Overproduction of UK-1 was obtained by growing a nataxazole non-producing mutant (lacking 6-methylsalicylate synthase, NatPK) in a zinc-deficient medium. Furthermore, Streptomyces sp. Tü 6176 also produces the siderophore enterobactin in an iron-free medium. Enterobactin production can be induced in an iron-independent manner by inactivating natAN, which encodes an anthranilate synthase involved in nataxazole production. The results indicate a close relationship between nataxazole, enterobactin and coelibactin pathways through the shikimate pathway, the source of their common precursor, chorismate.

Comparison of Lipoprotein-Associated Phospholipase A2 and High Sensitive C-Reactive Protein as Determinants of Metabolic Syndrome in Subjects without Coronary Heart Disease: In Search of the Best Predictor.

High sensitivity C-reactive protein (hsCRP) is a marker of metabolic syndrome (MS) and cardiovascular (CV) disease. Lipoprotein-associated phospholipase A2 (Lp-PLA2) also predicts CV disease. There are no reports comparing these markers as predictors of MS. Methods. Cross-sectional study comparing Lp-PLA2 and hsCRP as predictors of MS in asymptomatic subjects was carried out; 152 subjects without known atherosclerosis participated. Data were collected on demographics, cardiovascular risk factors, anthropometric and biochemical measurements, and hsCRP and Lp-PLA2 activity levels. A logistic regression analysis was performed with each biomarker and receiver operating characteristic (ROC) curves were constructed for MS. Results. Mean age was 46 ± 11 years, and 38% of the subjects had MS. Mean Lp-PLA2 activity was 185 ± 48 nmol/mL/min, and mean hsCRP was 2.1 ± 2.2 mg/L. Subjects with MS had significantly higher levels of Lp-PLA2 (P = 0.03) and hsCRP (P < 0.0001) than those without MS. ROC curves showed that both markers predicted MS. Conclusion. Lp-PLA2 and hsCRP are elevated in subjects with MS. Both biomarkers were independent and significant predictors for MS, emphasizing the role of inflammation in MS. Further research is necessary to determine if inflammation predicts a higher risk for CV events in MS subjects.

Genome Mining of Streptomyces sp. Tü 6176: Characterization of the Nataxazole Biosynthesis Pathway.

Streptomyces sp. Tü 6176 produces the cytotoxic benzoxazole nataxazole. Bioinformatic analysis of the genome of this organism predicts the presence of 38 putative secondary-metabolite biosynthesis gene clusters, including those involved in the biosynthesis of AJI9561 and its derivative nataxazole, the antibiotic hygromycin B, and ionophores enterobactin and coelibactin. The nataxazole biosynthesis gene cluster was identified and characterized: it lacks the O-methyltransferase gene required to convert AJI9561 into nataxazole. This O-methyltransferase activity might act as a resistance mechanism, as AJI9561 shows antibiotic activity whereas nataxazole is inactive. Moreover, heterologous expression of the nataxazole biosynthesis gene cluster in S. lividans JT46 resulted in the production of AJI9561. Nataxazole biosynthesis requires the shikimate pathway to generate 3-hydroxyanthranilate and an iterative type I PKS to generate 6-methylsalicylate. Production of nataxazole was improved up to fourfold by disrupting one regulatory gene in the cluster. An additional benzoxazole, 5-hydroxynataxazole is produced by Streptomyces sp. Tü 6176. 5-Hydroxynataxazole derives from nataxazole by the activity of an as yet unidentified oxygenase; this implies cross-talk between the nataxazole biosynthesis pathway and an unknown pathway.