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1.
Nat Prod Rep ; 37(1): 100-135, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074473

RESUMO

Covering: up to 2019Metabolic production of CO2 is natural product chemistry on a mammoth scale. Just counting humans, among all other respiring organisms, the seven billion people on the planet exhale about 3 billion tons of CO2 per year. Essentially all of the biogenic CO2 arises by action of discrete families of decarboxylases. The mechanistic routes to CO2 release from carboxylic acid metabolites vary with the electronic demands and structures of specific substrates and illustrate the breadth of chemistry employed for C-COO (C-C bond) disconnections. Most commonly decarboxylated are α-keto acid and ß-keto acid substrates, the former requiring thiamin-PP as cofactor, the latter typically cofactor-free. The extensive decarboxylation of amino acids, e.g. to neurotransmitter amines, is synonymous with the coenzyme form of vitamin B6, pyridoxal-phosphate, although covalent N-terminal pyruvamide residues serve in some amino acid decarboxylases. All told, five B vitamins (B1, B2, B3, B6, B7), ATP, S-adenosylmethionine, manganese and zinc ions are pressed into service for specific decarboxylase catalyses. There are additional cofactor-independent decarboxylases that operate by distinct chemical routes. Finally, while most decarboxylases use heterolytic ionic mechanisms, a small number of decarboxylases carry out radical pathways.

2.
Angew Chem Int Ed Engl ; 58(21): 6846-6879, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30156048

RESUMO

Enzyme-mediated cascade reactions are widespread in biosynthesis. To facilitate comparison with the mechanistic categorizations of cascade reactions by synthetic chemists and delineate the common underlying chemistry, we discuss four types of enzymatic cascade reactions: those involving nucleophilic, electrophilic, pericyclic, and radical reactions. Two subtypes of enzymes that generate radical cascades exist at opposite ends of the oxygen abundance spectrum. Iron-based enzymes use O2 to generate high valent iron-oxo species to homolyze unactivated C-H bonds in substrates to initiate skeletal rearrangements. At anaerobic end, enzymes reversibly cleave S-adenosylmethionine (SAM) to generate the 5'-deoxyadenosyl radical as a powerful oxidant to initiate C-H bond homolysis in bound substrates. The latter enzymes are termed radical SAM enzymes. We categorize the former as "thwarted oxygenases".

3.
Cell ; 175(1): 10-13, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30217361

RESUMO

This year's Lasker Clinical Research Award goes to James Baird Glen for the discovery and development of the anesthetic propofol. Patients benefit from its fast onset and rapid systemic clearance, eliminating the prolonged sedation effects experienced with earlier agents. In just 30 years, propofol has been adopted around the world for safe and controlled induction of anesthesia.


Assuntos
Propofol/farmacologia , Propofol/uso terapêutico , Anestesia/história , Anestesia/métodos , Distinções e Prêmios , História do Século XXI , Humanos , Propofol/história
4.
ACS Infect Dis ; 4(9): 1283-1299, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-29993235

RESUMO

Natural products with anti-infective activity are largely of polyketide or peptide origin. The nascent scaffolds typically undergo further enzymatic morphing to produce mature active structures. Two kinds of common constraints during maturation of immature scaffolds to active end point metabolites are macrocyclizations and hetrocyclizations. Each builds compact architectures characteristic of many high affinity, specific ligands for therapeutic targets. The chemical logic and enzymatic machinery for macrolactone and macrolactam formations are analyzed for antibiotics such as erythromycins, daptomycin, polymyxins, and vancomycin. In parallel, biosynthetic enzymes build small ring heterocycles, including epoxides, ß-lactams, and ß-lactones, cyclic ethers such as tetrahydrofurans and tetrahydropyrans, thiazoles, and oxazoles, as well as some seven- and eight-member heterocyclic rings. Combinations of fused heterocyclic scaffolds and heterocycles embedded in macrocycles reveal nature's chemical logic for building active molecular frameworks in short efficient pathways.


Assuntos
Antibacterianos/biossíntese , Antibacterianos/química , Produtos Biológicos/química , Compostos Heterocíclicos/química , Compostos Macrocíclicos/química , Bactérias/metabolismo , Produtos Biológicos/metabolismo , Vias Biossintéticas , Compostos Heterocíclicos/metabolismo , Compostos Macrocíclicos/metabolismo , Estrutura Molecular
6.
Biochemistry ; 57(22): 3087-3104, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29236467

RESUMO

Enzymes in biosynthetic pathways, especially in plant and microbial metabolism, generate structural and functional group complexity in small molecules by conversion of acyclic frameworks to cyclic scaffolds via short, efficient routes. The distinct chemical logic used by several distinct classes of cyclases, oxidative and non-oxidative, has recently been elucidated by genome mining, heterologous expression, and genetic and mechanistic analyses. These include enzymes performing pericyclic transformations, pyran synthases, tandem acting epoxygenases, and epoxide "hydrolases", as well as oxygenases and radical S-adenosylmethionine enzymes that involve rearrangements of substrate radicals under aerobic or anaerobic conditions.


Assuntos
Ciclização/fisiologia , Enzimas/fisiologia , Complexos Multienzimáticos/metabolismo , Animais , Fenômenos Bioquímicos/fisiologia , Vias Biossintéticas/fisiologia , Humanos , Redes e Vias Metabólicas/fisiologia , Complexos Multienzimáticos/fisiologia , Oxigenases/química
7.
Chem Rev ; 118(4): 1460-1494, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29272116

RESUMO

Contemporary analyses of cell metabolism have called out three metabolites: ATP, NADH, and acetyl-CoA, as sentinel molecules whose accumulation represent much of the purpose of the catabolic arms of metabolism and then drive many anabolic pathways. Such analyses largely leave out how and why ATP, NADH, and acetyl-CoA (Figure 1 ) at the molecular level play such central roles. Yet, without those insights into why cells accumulate them and how the enabling properties of these key metabolites power much of cell metabolism, the underlying molecular logic remains mysterious. Four other metabolites, S-adenosylmethionine, carbamoyl phosphate, UDP-glucose, and Δ2-isopentenyl-PP play similar roles in using group transfer chemistry to drive otherwise unfavorable biosynthetic equilibria. This review provides the underlying chemical logic to remind how these seven key molecules function as mobile packets of cellular currencies for phosphoryl transfers (ATP), acyl transfers (acetyl-CoA, carbamoyl-P), methyl transfers (SAM), prenyl transfers (IPP), glucosyl transfers (UDP-glucose), and electron and ADP-ribosyl transfers (NAD(P)H/NAD(P)+) to drive metabolic transformations in and across most primary pathways. The eighth key metabolite is molecular oxygen (O2), thermodynamically activated for reduction by one electron path, leaving it kinetically stable to the vast majority of organic cellular metabolites.


Assuntos
Redes e Vias Metabólicas , Termodinâmica , Acetilcoenzima A/metabolismo , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Glucose/metabolismo , Isomerismo , Cinética , NAD/metabolismo , NADP/metabolismo , Compostos de Fósforo/metabolismo , Processamento de Proteína Pós-Traducional , S-Adenosilmetionina/metabolismo
8.
Nat Prod Rep ; 34(7): 687-693, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28513710

RESUMO

Antibiotics are a therapeutic class that, once deployed, select for resistant bacterial pathogens and so shorten their useful life cycles. As a consequence new versions of antibiotics are constantly needed. Among the antibiotic natural products, morphed peptide scaffolds, converting conformationally mobile, short-lived linear peptides into compact, rigidified small molecule frameworks, act on a wide range of bacterial targets. Advances in bacterial genome mining, biosynthetic gene cluster prediction and expression, and mass spectroscopic structure analysis suggests many more peptides, modified both in side chains and peptide backbones, await discovery. Such molecules may turn up new bacterial targets and be starting points for combinatorial or semisynthetic manipulations to optimize activity and pharmacology parameters.


Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Genoma Microbiano , Peptídeos/farmacologia , Antibacterianos/química , Bactérias/metabolismo , Produtos Biológicos/química , Genoma Bacteriano , Estrutura Molecular , Família Multigênica , Peptídeos/química
9.
J Am Chem Soc ; 139(7): 2541-2544, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28170244

RESUMO

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.


Assuntos
Produtos Biológicos , Peptídeos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Compostos Macrocíclicos/química , Conformação Molecular , Simulação de Dinâmica Molecular , Peptídeos/genética , Peptídeos/farmacologia , Relação Estrutura-Atividade
10.
Annu Rev Biochem ; 86: 1-19, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28125288

RESUMO

After an undergraduate degree in biology at Harvard, I started graduate school at The Rockefeller Institute for Medical Research in New York City in July 1965. I was attracted to the chemical side of biochemistry and joined Fritz Lipmann's large, hierarchical laboratory to study enzyme mechanisms. That work led to postdoctoral research with Robert Abeles at Brandeis, then a center of what, 30 years later, would be called chemical biology. I spent 15 years on the Massachusetts Institute of Technology faculty, in both the Chemistry and Biology Departments, and then 26 years on the Harvard Medical School Faculty. My research interests have been at the intersection of chemistry, biology, and medicine. One unanticipated major focus has been investigating the chemical logic and enzymatic machinery of natural product biosynthesis, including antibiotics and antitumor agents. In this postgenomic era it is now recognized that there may be from 105 to 106 biosynthetic gene clusters as yet uncharacterized for potential new therapeutic agents.


Assuntos
Antibacterianos/metabolismo , Antineoplásicos/metabolismo , Bioquímica/história , Produtos Biológicos/metabolismo , Pesquisa Biomédica/história , Indústria Farmacêutica/história , Antibacterianos/química , Antineoplásicos/química , Bioquímica/tendências , Produtos Biológicos/química , Pesquisa Biomédica/tendências , Indústria Farmacêutica/tendências , Regulação da Expressão Gênica , História do Século XX , História do Século XXI , Humanos , Ligases/genética , Ligases/metabolismo , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Resistência a Vancomicina/genética , Recursos Humanos
11.
Chem Rev ; 117(8): 5226-5333, 2017 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-27936626

RESUMO

Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity, and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this Review, we examine the different strategies used by nature to create new intra(inter)molecular bonds via redox chemistry. This Review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, α-KG-dependent oxygenases, and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron manifolds in initiating cyclization reactions. The oxidative installations of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of "disappearing" reactive handles. Last, oxidative rearrangement of rings systems, including contractions and expansions, will be covered.


Assuntos
Produtos Biológicos/metabolismo , Ciclização , Enzimas/metabolismo , Oxirredução
12.
Proc Natl Acad Sci U S A ; 113(44): 12432-12437, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27791103

RESUMO

Epothilones are thiazole-containing natural products with anticancer activity that are biosynthesized by polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) enzymes EpoA-F. A cyclization domain of EpoB (Cy) assembles the thiazole functionality from an acetyl group and l-cysteine via condensation, cyclization, and dehydration. The PKS carrier protein of EpoA contributes the acetyl moiety, guided by a docking domain, whereas an NRPS EpoB carrier protein contributes l-cysteine. To visualize the structure of a cyclization domain with an accompanying docking domain, we solved a 2.03-Å resolution structure of this bidomain EpoB unit, comprising residues M1-Q497 (62 kDa) of the 160-kDa EpoB protein. We find that the N-terminal docking domain is connected to the V-shaped Cy domain by a 20-residue linker but otherwise makes no contacts to Cy. Molecular dynamic simulations and additional crystal structures reveal a high degree of flexibility for this docking domain, emphasizing the modular nature of the components of PKS-NRPS hybrid systems. These structures further reveal two 20-Å-long channels that run from distant sites on the Cy domain to the active site at the core of the enzyme, allowing two carrier proteins to dock with Cy and deliver their substrates simultaneously. Through mutagenesis and activity assays, catalytic residues N335 and D449 have been identified. Surprisingly, these residues do not map to the location of the conserved HHxxxDG motif in the structurally homologous NRPS condensation (C) domain. Thus, although both C and Cy domains have the same basic fold, their active sites appear distinct.


Assuntos
Epotilonas/química , Peptídeo Sintases/química , Policetídeo Sintases/química , Domínios Proteicos , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vias Biossintéticas/genética , Domínio Catalítico , Cristalografia por Raios X , Ciclização , Epotilonas/metabolismo , Modelos Moleculares , Myxococcales/genética , Myxococcales/metabolismo , Peptídeo Sintases/genética , Peptídeo Sintases/metabolismo , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Ligação Proteica , Homologia de Sequência de Aminoácidos , Tiazóis/química , Tiazóis/metabolismo
13.
Nat Prod Rep ; 33(2): 127-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26175103

RESUMO

Appreciation that some cyclic peptide antibiotics such as gramicidin S and tyrocidine were nonribosomally synthesized has been known for 50 years. The past two decades of research including advances in bacterial genetics, genomics, protein biochemistry and mass spectrometry have codified the principles of assembly line enzymology for hundreds of nonribosomal peptides and in parallel for thousands of polyketides. The advances in understanding the strategies used for chain initiation, elongation and termination from these assembly lines have revitalized natural product biosynthetic communities.


Assuntos
Bactérias/enzimologia , Produtos Biológicos/síntese química , Gramicidina/síntese química , Peptídeo Sintases/metabolismo , Peptídeos Cíclicos/síntese química , Policetídeos/química , Tirocidina/síntese química , Bactérias/metabolismo , Produtos Biológicos/química , Gramicidina/química , Estrutura Molecular , Peptídeos Cíclicos/química , Tirocidina/química
15.
Synlett ; 26(8): 1008-1025, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26207083

RESUMO

In vitro analysis of metabolic pathways is becoming a powerful method to gain a deeper understanding of Nature's core biochemical transformations. With astounding advancements in biotechnology, purification of a metabolic pathway's constitutive enzymatic components is becoming a tractable problem, and such in vitro studies allow scientists to capture the finer details of enzymatic reaction mechanisms, kinetics, and the identity of organic product molecules. In this review, we present eleven metabolic pathways that have been the subject of in vitro reconstitution studies in the literature in recent years. In addition, we have selected and analyzed subset of four case studies within these eleven examples that exemplify remarkable organic chemistry occurring within biology. These examples serves as tangible reminders that Nature's biochemical routes obey the fundamental principles of organic chemistry, and the chemical mechanisms are reminiscent of those featured in traditional synthetic organic routes. The illustrations of biosynthetic chemistry depicted in this review may inspire the development of biomimetic chemistries via abiotic chemical techniques.

16.
BMC Struct Biol ; 15: 13, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26170207

RESUMO

BACKGROUND: Calicheamicins (CAL) are enedyine natural products with potent antibiotic and cytotoxic activity, used in anticancer therapy. The O-methyltransferase CalO6 is proposed to catalyze methylation of the hydroxyl moiety at the C2 position of the orsellinic acid group of CAL. RESULTS: Crystals of CalO6 diffracted non-isotropically, with the usable data extending to 3.4 Å. While no single method of crystal structure determination yielded a structure of CalO6, we were able to determine its structure by using molecular replacement-guided single wavelength anomalous dispersion by using diffraction data from native crystals of CalO6 and a highly non-isomorphous mercury derivative. The structure of CalO6 reveals the methyltransferase fold and dimeric organization characteristic of small molecule O-methyltransferases involved in secondary metabolism in bacteria and plants. Uncommonly, CalO6 was crystallized in the absence of S-adenosylmethionine (SAM; the methyl donor) or S-adenosylhomocysteine (SAH; its product). CONCLUSIONS: Likely as a consequence of the dynamic nature of CalO6 in the absence of its cofactor, the central region of CalO6, which forms a helical lid-like structure near the active site in CalO6 and similar enzymes, is not observed in the electron density. We propose that this region controls the entry of SAM into and the exit of SAH from the active site of CalO6 and shapes the active site for substrate binding and catalysis.


Assuntos
Aminoglicosídeos/biossíntese , Proteínas de Bactérias/química , Micromonospora/enzimologia , Proteína O-Metiltransferase/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Micromonospora/genética , Micromonospora/metabolismo , Modelos Moleculares , Dobramento de Proteína , Proteína O-Metiltransferase/genética , Proteína O-Metiltransferase/metabolismo , Estrutura Secundária de Proteína , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo
17.
Front Microbiol ; 6: 170, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25814981

RESUMO

The Pseudomonas aeruginosa toxin L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) is a non-proteinogenic amino acid which is toxic for prokaryotes and eukaryotes. Production of AMB requires a five-gene cluster encoding a putative LysE-type transporter (AmbA), two non-ribosomal peptide synthetases (AmbB and AmbE), and two iron(II)/α-ketoglutarate-dependent oxygenases (AmbC and AmbD). Bioinformatics analysis predicts one thiolation (T) domain for AmbB and two T domains (T1 and T2) for AmbE, suggesting that AMB is generated by a processing step from a precursor tripeptide assembled on a thiotemplate. Using a combination of ATP-PPi exchange assays, aminoacylation assays, and mass spectrometry-based analysis of enzyme-bound substrates and pathway intermediates, the AmbB substrate was identified to be L-alanine (L-Ala), while the T1 and T2 domains of AmbE were loaded with L-glutamate (L-Glu) and L-Ala, respectively. Loading of L-Ala at T2 of AmbE occurred only in the presence of AmbB, indicative of a trans loading mechanism. In vitro assays performed with AmbB and AmbE revealed the dipeptide L-Glu-L-Ala at T1 and the tripeptide L-Ala-L-Glu-L-Ala attached at T2. When AmbC and AmbD were included in the assay, these peptides were no longer detected. Instead, an L-Ala-AMB-L-Ala tripeptide was found at T2. These data are in agreement with a biosynthetic model in which L-Glu is converted into AMB by the action of AmbC, AmbD, and tailoring domains of AmbE. The importance of the flanking L-Ala residues in the precursor tripeptide is discussed.

19.
ACS Chem Biol ; 9(12): 2718-28, 2014 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-25303280

RESUMO

The indole side chain of tryptophan has latent nucleophilic reactivity at both N1 and all six (nonbridgehead) carbons, which is not generally manifested in post-translational reactions of proteins. On the other hand, all seven positions can be prenylated by the primary metabolite Δ(2)-isopentenyl diphosphate by dimethyallyl transferase (DMATs) family members as initial steps in biosynthetic pathways to bioactive fungal alkaloids including ergots and tremorgens. These are formulated as regioselective capture of isopentenyl allylic cationic transition states by the indole side chain as a nucleophile. The balance of regiospecificity and promiscuity among these indole prenyltransferases continues to raise questions about possible Cope and azaCope rearrangements of nascent products. In addition to these two electron reaction manifolds, there is evidence for one electron reaction manifolds in indole ring biosynthetic functionalization.


Assuntos
Alquil e Aril Transferases/metabolismo , Proteínas de Bactérias/metabolismo , Dimetilaliltranstransferase/metabolismo , Proteínas Fúngicas/metabolismo , Indóis/química , Terpenos/química , Triptofano/metabolismo , Bactérias/metabolismo , Alcaloides de Claviceps/biossíntese , Alcaloides de Claviceps/química , Fungos/metabolismo , Hemiterpenos/química , Hemiterpenos/metabolismo , Indóis/metabolismo , Estrutura Molecular , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , Prenilação , Estereoisomerismo , Especificidade por Substrato , Terpenos/metabolismo , Triptofano/química
20.
Biochemistry ; 53(38): 6063-77, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25184411

RESUMO

The soil actinomycete Kutzneria sp. 744 produces a class of highly decorated hexadepsipeptides, which represent a new chemical scaffold that has both antimicrobial and antifungal properties. These natural products, known as kutznerides, are created via nonribosomal peptide synthesis using various derivatized amino acids. The piperazic acid moiety contained in the kutzneride scaffold, which is vital for its antibiotic activity, has been shown to derive from the hydroxylated product of l-ornithine, l-N(5)-hydroxyornithine. The production of this hydroxylated species is catalyzed by the action of an FAD- and NAD(P)H-dependent N-hydroxylase known as KtzI. We have been able to structurally characterize KtzI in several states along its catalytic trajectory, and by pairing these snapshots with the biochemical and structural data already available for this enzyme class, we propose a structurally based reaction mechanism that includes novel conformational changes of both the protein backbone and the flavin cofactor. Further, we were able to recapitulate these conformational changes in the protein crystal, displaying their chemical competence. Our series of structures, with corroborating biochemical and spectroscopic data collected by us and others, affords mechanistic insight into this relatively new class of flavin-dependent hydroxylases and adds another layer to the complexity of flavoenzymes.


Assuntos
Actinobacteria/enzimologia , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Flavina-Adenina Dinucleotídeo/metabolismo , Oxigenases de Função Mista/metabolismo , Actinobacteria/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Domínio Catalítico , Cristalização , Regulação Bacteriana da Expressão Gênica , Oxigenases de Função Mista/genética , Modelos Moleculares , NADP/metabolismo , Oxirredução , Conformação Proteica
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