Biosynthesis of polyether and aminoglycoside antibiotics: structural investigation of unusual enzymes or with synthetic biology applicability

• Grant number: 15/09188-8
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2016
• End date: January 31, 2019
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Marcio Vinicius Bertacine Dias
• Grantee: Marcio Vinicius Bertacine Dias
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant(s): 17/50140-4 - Mechanisms of ring formation in inophore polyether tetronates, AP.R SPRINT

Abstract

Natural products are an important source of molecules that are used by humans to treat various diseases, such as cancer and infectious diseases. These molecules generally are derivatives of secondary metabolism of microorganisms and plants through of sophisticated biosynthetic systems. However, the mechanism of how those enzymes, which are in gene clusters, act to produce specific compounds are not well understood. In this project, we aim to continue the work that has been done by our research group in last years in the understanding of two different classes of natural products. We intend to continue our studies about the biosynthesis of gentamicin and sisomicin, two aminoglycoside which are widely aminated and methylated and largely used in the medicine to threat bacterial infections, although their nephro and ototoxicity. In this part of the project, we expect to obtain tridimensional structures of specific aminotransferases, methyltransferases and dihydrogenases for the biosynthesis of this class of antibiotics and understand their mechanism of catalysis through of structure analysis of protein complexes with ligand and substrate analogues. In parallel, we will also expect to continue our studies about the biosynthesis of another group of natural compounds, which are the polycyclic polyether ionophores. We will keep working to obtain further understanding of specific and very peculiar epoxide hydrolases on the biosynthesis of those compounds. Thus, we expect to extend and deepen the study of those enzymes and about epoxidases seeking to understand the intriguing mechanism of cyclic ethers closure of these compounds. In the end of this project, we expect to contribute to generate crucial information into the context of chemistry biology and add knowledge that might be useful for synthetic biology to produce new less toxic derivatives of antibiotic for human and animal therapy. (AU)

Scientific publications

(12)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BERTACINE DIAS, MARCIO V.; SANTOS, JADEMILSON C.; LIBREROS-ZUNIGA, GERARDO A.; RIBEIRO, JOAO A.; CHAVEZ-PACHECO, SAIR M.. Folate biosynthesis pathway: mechanisms and insights into drug design for infectious diseases. Future Medicinal Chemistry, v. 10, n. 8, p. 935-959, APR 2018. (15/09188-8, 13/15906-5, 10/15971-3)

DE OLIVEIRA, GABRIEL S.; ADRIANI, PATRICIA P.; RIBEIRO, JOAO AUGUSTO; MORISSEAU, CHRISTOPHE; HAMMOCK, BRUCE D.; DIAS, MARCIO VINICIUS B.; CHAMBERGO, FELIPE S.. The molecular structure of an epoxide hydrolase from Trichoderma reesei in complex with urea or amide-based inhibitors. International Journal of Biological Macromolecules, v. 129, p. 653-658, MAY 15 2019. (13/15906-5, 16/12859-4, 15/03329-9, 15/09188-8, 18/00351-1, 14/24107-1, 17/25705-8)

KIRKMAN, TIM; FUN TAN, SUK; CHAVEZ-PACHECO, SAIR MAXIMO; HAMMER, ALEXANDER; ABELL, CHRIS; TOSIN, MANUELA; COYNE, ANTHONY G.; DIAS, MARCIO V. B.. Fragment-Merging Strategies with Known Pyrimidine Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis. CHEMMEDCHEM, v. 18, n. 15, p. 9-pg., 2023-06-06. (20/03850-9, 15/09188-8)

RIBEIRO, JOAO AUGUSTO; CHAVEZ-PACHECO, SAIR MAXIMO; DE OLIVEIRA, GABRIEL STEPHANI; SILVA, CATHARINA DOS SANTOS; PIMENTA GIUDICE, JOAO HENRIQUE; LIBREROS-ZUNIGA, GERARDO ANDRES; BERTACINE DIAS, MARCIO VINICIUS. Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, n. 7, p. 682-693, JUL 2019. (13/15906-5, 15/09188-8, 18/00351-1, 14/24486-2, 16/18721-4)

DE ARAUJO, NATALIA CERRONE; BURY, PRISCILA DOS SANTOS; TAVARES, MAURICIO TEMOTHEO; HUANG, FANGLU; PARISE-FILHO, ROBERTO; LEADLAY, PETER; BERTACINE DIAS, MARCIO VINICIUS. Crystal Structure of GenD2, an NAD-Dependent Oxidoreductase Involved in the Biosynthesis of Gentamicin. ACS Chemical Biology, v. 14, n. 5, p. 925-933, MAY 2019. (10/15971-3, 15/09188-8, 14/07843-6, 14/50324-0)

BURY, PRISCILA DOS SANTOS; HUANG, FANGLU; LI, SICONG; SUN, YUHUI; LEADLAY, PETER F.; BERTACINE DIAS, MARCIO VINICIUS. Structural Basis of the Selectivity of GenN, an Aminoglycoside N-Methyltransferase Involved in Gentamicin Biosynthesis. ACS Chemical Biology, v. 12, n. 11, p. 2779-2787, NOV 2017. (14/07843-6, 10/15971-3, 15/09188-8, 14/50324-0)

LITTLE, RORY; PAIVA, FERNANDA C. R.; JENKINS, ROBERT; HONG, HUI; SUN, YUHUI; DEMYDCHUK, YULIYA; SAMBORSKYY, MARKIYAN; TOSIN, MANUELA; LEEPER, FINIAN J.; DIAS, MARCIO V. B.; et al. Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis. NATURE CATALYSIS, v. 2, n. 11, p. 1045-1054, NOV 2019. (15/09188-8, 17/50140-4, 18/00351-1)

WILSON, CAROLINA; DE OLIVEIRA, GABRIEL S.; ADRIANI, PATRICIA P.; CHAMBERGO, FELIPE S.; DIAS, MARCIO V. B.. Structure of a soluble epoxide hydrolase identified in Trichoderma reesei. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1865, n. 8, p. 1039-1045, AUG 2017. (15/09188-8, 10/15971-3, 14/24107-1, 15/03329-9)

LIBREROS-ZUNIGA, GERARDO ANDRES; SILVA, CATHARINA DOS SANTOS; FERREIRA, RAFAELA SALGADO; BERTACINE DIAS, MARCIO VINICIUS. Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by L,D-Transpeptidase 3 (Ldt(Mt3)) from Mycobacterium tuberculosis. ACS INFECTIOUS DISEASES, v. 5, n. 2, p. 260-271, FEB 2019. (15/09188-8, 10/15971-3, 16/18721-4)

LI, SICONG; BURY, PRISCILA DOS SANTOS; HUANG, FANGLU; GUO, JUNHONG; SUN, GUO; REVA, ANNA; HUANG, CHUAN; JIAN, XINYUN; LI, YUAN; ZHOU, JIAHAI; et al. Mechanistic Insights into Dideoxygenation in Gentamicin Biosynthesis. ACS CATALYSIS, v. 11, n. 19, p. 12274-12283, OCT 1 2021. (14/07843-6, 15/09188-8, 10/15971-3, 18/00351-1)

TORMET-GONZALEZ, GABRIELA D.; WILSON, CAROLINA; DE OLIVEIRA, GABRIEL STEPHANI; DOS SANTOS, JADEMILSON CELESTINO; DE OLIVEIRA, LUCIANA G.; DIAS, MARCIO VINICIUS BERTACINE. An epoxide hydrolase from endophytic Streptomycess hows unique structural features and wide biocatalytic activity. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 76, p. 8-pg., 2020-09-01. (19/10564-5, 18/00351-1, 15/09188-8, 11/06209-3, 14/50249-8, 10/15971-3, 13/26242-0, 14/12727-5)

RIBEIRO, JOAO AUGUSTO; CHAVEZ-PACHECO, SAIR MAXIMO; DE OLIVEIRA, GABRIEL STEPHANI; SILVA, CATHARINA DOS SANTOS; PIMENTA GIUDICE, JOAO HENRIQUE; LIBREROS-ZUNIGA, GERARDO ANDRES; BERTACINE DIAS, MARCIO VINICIUS. Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, p. 12-pg., 2019-07-01. (13/15906-5, 18/00351-1, 15/09188-8, 14/24486-2, 16/18721-4)