ABSTRACT
The marine sponge Aka coralliphaga is a rich source of biologically active and structurally interesting meroterpenoids. Inspired by these natural products, we have used biosynthetic speculation to devise biomimetic syntheses of siphonodictyal B, liphagal and corallidictyals A-D from sclareolide. This work resulted in the development of new cascade reactions in the synthesis of liphagal, the reassignment of the structure of siphonodictyal B, and the realisation that corallidictyals A and B are possibly isolation artefacts.
Subject(s)
Biological Products/chemistry , Hydroquinones/chemical synthesis , Porifera/chemistry , Sesquiterpenes/chemical synthesis , Terpenes/chemical synthesis , Animals , Biological Products/chemical synthesis , Biomimetics , Cyclization , Diterpenes/chemistry , Hydroquinones/chemistry , Oxidation-Reduction , Porifera/metabolism , Sesquiterpenes/chemistry , Terpenes/chemistryABSTRACT
Isopenicillin N synthase (IPNS) catalyses the four-electron oxidation of a tripeptide, l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV), to give isopenicillin N (IPN), the first-formed ß-lactam in penicillin and cephalosporin biosynthesis. IPNS catalysis is dependent upon an iron(II) cofactor and oxygen as a co-substrate. In the absence of substrate, the carbonyl oxygen of the side-chain amide of the penultimate residue, Gln330, co-ordinates to the active-site metal iron. Substrate binding ablates the interaction between Gln330 and the metal, triggering rearrangement of seven C-terminal residues, which move to take up a conformation that extends the final α-helix and encloses ACV in the active site. Mutagenesis studies are reported, which probe the role of the C-terminal and other aspects of the substrate binding pocket in IPNS. The hydrophobic nature of amino acid side-chains around the ACV binding pocket is important in catalysis. Deletion of seven C-terminal residues exposes the active site and leads to formation of a new type of thiol oxidation product. The isolated product is shown by LC-MS and NMR analyses to be the ene-thiol tautomer of a dithioester, made up from two molecules of ACV linked between the thiol sulfur of one tripeptide and the oxidised cysteinyl ß-carbon of the other. A mechanism for its formation is proposed, supported by an X-ray crystal structure, which shows the substrate ACV bound at the active site, its cysteinyl ß-carbon exposed to attack by a second molecule of substrate, adjacent. Formation of this product constitutes a new mode of reaction for IPNS and non-heme iron oxidases in general.
Subject(s)
Aldehydes/metabolism , Esters/metabolism , Oxidoreductases/metabolism , Sulfhydryl Compounds/chemistry , Aldehydes/chemistry , Binding Sites , Biocatalysis , Catalytic Domain , Cephalosporins/biosynthesis , Cephalosporins/chemistry , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Esters/chemistry , Iron/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Conformation , Mutagenesis , Oxidation-Reduction , Oxidoreductases/genetics , Oxygen/chemistry , Oxygen/metabolism , Penicillins/biosynthesis , Penicillins/chemistry , Substrate SpecificityABSTRACT
Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of ß-lactam antibiotics. IPNS converts the tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue δ-(L-α-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS. Epimeric δ-(L-α-aminoadipoyl)-L-cysteinyl-O-methyl-D-allo-threonine (ACmaT) is converted to a bioactive penam product. ACmT and ACmaT differ from each other only in the stereochemistry at the ß-carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X-ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen-bonding to the ether oxygen atom of the substrate analogue.
Subject(s)
Oxidoreductases/chemistry , Water/chemistry , Anti-Bacterial Agents/chemistry , Binding Sites , Crystallography, X-Ray , Ligands , Methyl Ethers/chemistry , Models, Molecular , Oxygen/chemistry , Penicillins/chemistry , Protein Binding , Protein Conformation , Stereoisomerism , Substrate Specificity , beta-LactamsABSTRACT
Isopenicillin N synthase (IPNS) converts the linear tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a diverse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products; this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation. To investigate this and solution-phase results with other tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa, we have crystallised AhCV and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:Fe(II):AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:Fe(II):AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures.
Subject(s)
Homocysteine/chemistry , Oxidoreductases/metabolism , Penicillins/biosynthesis , Biocatalysis , Catalytic Domain , Crystallography, X-Ray , Ferrous Compounds/chemistry , Homocysteine/metabolism , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/metabolism , Oxidoreductases/chemistry , Substrate SpecificityABSTRACT
Isopenicillin N synthase (IPNS) converts its linear tripeptide substrate δ-L-α-aminoadipoyl-L-cysteinyl-D-valine (ACV) to bicyclic isopenicillin N (IPN), the key step in penicillin biosynthesis. Solution-phase incubation experiments have shown that IPNS will accept and oxidise a diverse array of substrate analogues, including tripeptides that incorporate L-homocysteine as their second residue, and tripeptides with truncated side-chains at the third amino acid such as δ-L-α-aminoadipoyl-L-cysteinyl-D-α-aminobutyrate (ACAb), δ-L-α-aminoadipoyl-L-cysteinyl-D-alanine (ACA) and δ-L-α-aminoadipoyl-L-cysteinyl-glycine (ACG). However IPNS does not react with dipeptide substrates. To probe this selectivity we have crystallised the enzyme with the dipeptide δ-L-α-aminoadipoyl-L-homocysteine (AhC) and solved a crystal structure for the IPNS:Fe(II):AhC complex to 1.40 Å resolution. This structure reveals an unexpected mode of peptide binding at the IPNS active site, in which the homocysteinyl thiolate does not bind to iron. Instead the primary mode of binding sees the homocysteinyl carboxylate coordinated to the metal, while its side-chain is oriented into the region of the active site normally occupied by the benzyl group of protein residue Phe211.
Subject(s)
Dipeptides/chemistry , Dipeptides/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Catalytic Domain , Crystallography, X-Ray , Homocysteine/chemistry , Homocysteine/metabolism , Iron/metabolism , Models, Molecular , Protein Conformation , Sequence DeletionABSTRACT
Three new sterically demanding ligands based on the bispyrazolylacetic acid motif have been prepared and complexes with Fe(II), Fe(III), Ni(II) and Mn(II) have been synthesised and characterised. Single crystal X-ray structures are included for two of the ligands in the protonated form and ten other complexes. Additionally, a new general route to amide derivatives has been established, a range of amide derivatives synthesised and their coordination chemistry investigated. Only one metal complex was synthesised from the amide ligands, and was bound via the hydroxylamine groups in preference to the pyrazole and carboxylate donor set.
ABSTRACT
Isopenicillin N synthase (IPNS) catalyses cyclization of δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to isopenicillin N (IPN), the central step in penicillin biosynthesis. Previous studies have shown that IPNS turns over a wide range of substrate analogues in which the valine residue of its natural substrate is replaced with other amino acids. IPNS accepts and oxidizes numerous substrates that bear hydrocarbon sidechains in this position, however the enzyme is less tolerant of analogues presenting polar functionality in place of the valinyl isopropyl group. We report a new ACV analogue δ-(l-α-aminoadipoyl)-l-cysteinyl-d-methionine (ACM), which incorporates a thioether in place of the valinyl sidechain. ACM has been synthesized using solution phase methods and crystallized with IPNS. A crystal structure has been elucidated for the IPNS:Fe(II):ACM complex at 1.40Å resolution. This structure reveals that ACM binds in the IPNS active site such that the sulfur atom of the methionine thioether binds to iron in the oxygen binding site at a distance of 2.57Å. The sulfur of the cysteinyl thiolate sits 2.36Å from the metal.
Subject(s)
Oligopeptides/chemistry , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Catalytic Domain , Crystallography, X-Ray , Iron/chemistry , Methionine/analogs & derivatives , Methionine/chemistry , Models, Molecular , Oligopeptides/chemical synthesis , Static Electricity , Substrate Specificity , Sulfides/chemistryABSTRACT
Isopenicillin N synthase (IPNS) catalyses the synthesis of isopenicillin N (IPN), the biosynthetic precursor to penicillin and cephalosporin antibiotics. IPNS is a non-heme iron(II) oxidase that mediates the oxidative cyclisation of the tripeptide δ-L-α-aminoadipoyl-L-cysteinyl-D-valine (ACV) to IPN with a concomitant reduction of molecular oxygen to water. Solution-phase incubation experiments have shown that, although IPNS can turn over analogues with a diverse range of hydrocarbon side chains in the third (valinyl) position of its substrate, the enzyme is much less tolerant of polar residues in this position. Thus, although IPNS converts δ-L-α-aminoadipoyl-L-cysteinyl-D-isoleucine (ACI) and AC-D-allo-isoleucine (ACaI) to penam products, the isosteric sulfur-containing peptides AC-D-thiaisoleucine (ACtI) and AC-D-thia-allo-isoleucine (ACtaI) are not turned over. To determine why these peptides are not substrates, we crystallized ACtaI with IPNS. We report the synthesis of ACtaI and the crystal structure of the IPNS:Fe(II) :ACtaI complex to 1.79 Å resolution. This structure reveals direct ligation of the thioether side chain to iron: the sulfide sulfur sits 2.66 Å from the metal, squarely in the oxygen binding site. This result articulates a structural basis for the failure of IPNS to turn over these substrates.
Subject(s)
Biochemistry/methods , Fungal Proteins/metabolism , Isoleucine , Oxidoreductases/metabolism , Penicillins/biosynthesis , Binding Sites , Crystallography, X-Ray , Fungal Proteins/chemistry , Hydrophobic and Hydrophilic Interactions , Iron/metabolism , Isoleucine/analogs & derivatives , Isoleucine/metabolism , Models, Molecular , Oligopeptides/chemistry , Oligopeptides/metabolism , Oxidation-Reduction , Oxidoreductases/chemistry , Oxygen , Penicillins/chemistry , Protein Binding , Substrate Specificity , Sulfur/metabolism , Valine/chemistry , Valine/metabolismABSTRACT
Isopenicillin N synthase (IPNS) is a non-heme iron(II) oxidase which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-valine (lld-ACV). Herein we report crystallographic studies to investigate the binding of a truncated lll-substrate in the active site of IPNS. Two epimeric tripeptides have been prepared by solution phase peptide synthesis and crystallised with the enzyme. delta-l-alpha-Aminoadipoyl-l-cysteinyl-d-2-amino-3,3-dideuteriobutyrate (lld-ACd(2)Ab) has the same configuration as the natural substrate lld-ACV at each of its three stereocentres; its epimer delta-l-alpha-aminoadipoyl-l-cysteinyl-l-2-amino-3,3-dideuteriobutyrate (lll-ACd(2)Ab) has the opposite configuration at its third amino acid. lll-ACV has previously been shown to inhibit IPNS turnover of its substrate lld-ACV; the all-protiated tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-2-aminobutyrate (lld-ACAb) is a substrate for IPNS, being turned over to a mixture of penam and cepham products. Comparisons between the crystal structures of the IPNS:Fe(II):lld-ACd(2)Ab and IPNS:Fe(II):lll-ACd(2)Ab complexes offer a possible rationale for the previously observed inhibitory effects of lll-ACV on IPNS activity.
Subject(s)
Oligopeptides/chemistry , Oxidoreductases/chemistry , Catalytic Domain , Crystallography, X-Ray , Deuterium/chemistry , Oxidoreductases/antagonists & inhibitorsABSTRACT
Biomimetic syntheses of three polycylic polyprenylated acylphloroglucinol natural products isolated from Hypericum papuanum, ialibinone A, ialibinone B, and hyperguinone B, have been accomplished by selective oxidative cyclizations of the proposed biosynthetic precursor 5, which was synthesized from phloroglucinol in three steps.
Subject(s)
Biological Products/chemical synthesis , Hypericum/chemistry , Phloroglucinol/analogs & derivatives , Phloroglucinol/chemistry , Polycyclic Aromatic Hydrocarbons/chemical synthesis , Biological Products/chemistry , Biological Products/isolation & purification , Cyclization , Molecular Structure , Oxidation-Reduction , Polycyclic Aromatic Hydrocarbons/chemistry , Polycyclic Aromatic Hydrocarbons/isolation & purificationABSTRACT
A biosynthetically inspired synthesis of (+)-liphagal has been achieved from (+)-sclareolide in 13 steps (9% overall yield). The key step is a biomimetic ring expansion of a highly stabilized benzylic carbocation, which generates the seven-membered ring and the benzofuran of the natural product in a single cascade reaction.
Subject(s)
Terpenes/chemical synthesis , Diterpenes/chemistry , Molecular Conformation , Stereoisomerism , Terpenes/chemistryABSTRACT
The biosynthesis of the meroterpenoid guajadial was previously hypothesized to occur via a hetero-Diels-Alder reaction between caryophyllene and an o-quinone methide. This hypothesis has been verified via the biomimetic synthesis of guajadial and psidial A in an aqueous three-component coupling reaction, between caryophyllene, benzaldehyde, and diformylphloroglucinol.
Subject(s)
Biomimetics , Sesquiterpenes/chemical synthesis , Terpenes/chemical synthesis , Models, Molecular , Molecular Conformation , Sesquiterpenes/chemistry , Terpenes/chemistryABSTRACT
Isopenicillin N synthase (IPNS) is a non-heme iron(ii) oxidase, which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-valine (lld-ACV) in a remarkable oxidative bicyclisation reaction. The natural substrate for IPNS is the lld-configured tripeptide. lll-ACV is not turned over by the enzyme, but inhibits turnover of the lld-tripeptide. The mechanism by which this inhibition takes place is not fully understood. Recent studies have employed a range of lld-configured depsipeptide substrate analogues in crystallographic studies to probe events preceding beta-lactam closure in the IPNS reaction cycle. Herein, we report the first crystal structure of IPNS in complex with an lll-configured depsipeptide analogue, delta-l-alpha-aminoadipoyl-l-cysteine (1-(R)-carboxy-2-thiomethyl)ethyl ester (lll-ACOmC). This report describes the crystal structure of the IPNS:Fe(ii):lll-ACOmC complex to 2.0 A resolution, and discusses attempts to oxygenate this complex at high pressure in order to probe the mechanism by which lll-configured substrates inhibit IPNS catalysis.
Subject(s)
Aspergillus nidulans/chemistry , Crystallography, X-Ray , Depsipeptides/chemistry , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Aspergillus nidulans/metabolism , Catalytic Domain , Depsipeptides/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Substrate SpecificityABSTRACT
Isopenicillin N synthase (IPNS) is a nonheme iron(II)-dependent oxidase that catalyses the central step in penicillin biosynthesis, conversion of the tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN). This report describes mechanistic studies using the analogue delta-(L-alpha-aminoadipoyl)-(3S-methyl)-L-cysteine D-alpha-hydroxyisovaleryl ester (A(S)mCOV), designed to intercept the catalytic cycle at an early stage. A(S)mCOV incorporates two modifications from the natural substrate: the second and third residues are joined by an ester, so this analogue lacks the key amide of ACV and cannot form a beta-lactam; and the cysteinyl residue is substituted at its beta-carbon, bearing a (3S)-methyl group. It was anticipated that this methyl group will impinge directly on the site in which the co-substrate dioxygen binds. The novel depsipeptide A(S)mCOV was prepared in 13 steps and crystallised with IPNS anaerobically. The 1.65 A structure of the IPNS-Fe(II)-A(S)mCOV complex reveals that the additional beta-methyl group is not oriented directly into the oxygen binding site, but does increase steric demand in the active site and increases disorder in the position of the isovaleryl side chain. Crystals of IPNS-Fe(II)-A(S)mCOV were incubated with high-pressure oxygen gas, driving substrate turnover to a single product, an ene-thiol/C-hydroxylated depsipeptide. A mechanism is proposed for the reaction of A(S)mCOV with IPNS, linking this result to previous crystallographic studies with related depsipeptides and solution-phase experiments with cysteine-methylated tripeptides. This result demonstrates that a (3S)-methyl group at the substrate cysteinyl beta-carbon is not in itself a block to IPNS activity as previously proposed, and sheds further light on the steric complexities of IPNS catalysis.
Subject(s)
Depsipeptides/chemistry , Depsipeptides/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Biocatalysis , Molecular Structure , Oligopeptides/chemistry , Oligopeptides/metabolismABSTRACT
Mechanistic investigations of biological enzymatic processes require controlled initiation and monitoring of catalytic reactions. A well-known technique to trap and observe reaction intermediates building up along a reaction pathway is the use of low temperature conditions. Here, we report a kinetically competent system for the release of molecular oxygen at cryogenic temperature, using a cobalt-based caged oxygen molecule, (micro-peroxo)(micro-hydroxo)bis[bis(bipyridyl)cobalt(III)] nitrate. Cryophotolysis of this compound was induced using 266 nm laser light and monitored by absorption microspectrophotometry. Furthermore, to verify that photo-fragmentation was accompanied by release of the active caged molecule, the production of dioxygen during cryophotolysis was directly visualized. This work lays the foundations for the use of low temperature reaction triggering as a tool to prolong the lifetime of normally unstable intermediate states in oxygen-dependent enzymes.
Subject(s)
Cold Temperature , Organometallic Compounds/chemistry , Oxygen/chemistry , Photolysis , Crystallography, X-Ray , Kinetics , Models, Molecular , Molecular Structure , Nitrates/chemical synthesis , Nitrates/chemistry , Organometallic Compounds/chemical synthesisABSTRACT
Isopenicillin N synthase (IPNS) is a nonheme iron oxidase that catalyzes the central step in the biosynthesis of beta-lactam antibiotics: oxidative cyclization of the linear tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN). The ACV analogue delta-L-alpha-aminoadipoyl-L-cysteine (1-(S)-carboxy-2-thiomethyl)ethyl ester (ACOmC) has been synthesized as a mechanistic probe of IPNS catalysis and crystallized with the enzyme. The crystal structure of the anaerobic IPNS/Fe(II)/ACOmC complex was determined to 1.80 A resolution, revealing a highly congested active site region. By exposing these anaerobically grown crystals to high-pressure oxygen gas, an unexpected sulfenate product has been observed, complexed to iron within the IPNS active site. A mechanism is proposed for formation of the sulfenate-iron complex, and it appears that ACOmC follows a different reaction pathway at the earliest stages of its reaction with IPNS. Thus it seems that oxygen (the cosubstrate) binds in a different site to that observed in previous studies with IPNS, displacing a water ligand from iron in the process. The iron-mediated conversion of metal-bound thiolate to sulfenate has not previously been observed in crystallographic studies with IPNS. This mode of reactivity is of particular interest when considered in the context of another family of nonheme iron enzymes, the nitrile hydratases, in which post-translational oxidation of two cysteine thiolates to sulfenic and sulfinic acids is essential for enzyme activity.
Subject(s)
Depsipeptides/chemical synthesis , Oxidoreductases/metabolism , Sulfenic Acids/chemical synthesis , Cyclization , Hydro-Lyases , Oxidation-Reduction , Oxygen , Sulfhydryl Compounds/chemistryABSTRACT
Our biomimetic hypothesis proposes that families of diverse natural products with complex core structures such as 9,10-deoxytridachione, photodeoxytridachione and ocellapyrone A are derived in nature from a linear and conformationally strained all-( E) tetraene-pyrone precursor. We therefore synthesized such a precursor and investigated its biomimetic transformation under a variety of reaction conditions, both to the above natural products as well as to diverse isomers which we propose to be natural products "yet to be discovered". We also report herein the first synthesis of the natural product iso-9,10-deoxytridachione.
Subject(s)
Biological Products/chemical synthesis , Macrolides/chemistry , Pyrones/chemical synthesis , Models, Molecular , Molecular Structure , Propionates/chemistry , Propionates/metabolismABSTRACT
A carbocyclic analogue of the beta-lactam antibiotic isopenicillin N (IPN) has been synthesised and cocrystallised with isopenicillin N synthase (IPNS), the central enzyme in the biosynthesis of penicillin antibiotics. The crystal structure of the IPNS-cyclobutanone complex reveals an active site environment similar to that seen in the enzyme-product complex generated by turnover of the natural substrate within the crystalline protein. The IPNS-cyclobutanone structure demonstrates that the product analogue is tethered to the protein by hydrogen bonding and salt bridge interactions with its carboxylate groups, as seen previously for the natural substrate and product. Furthermore, the successful cocrystallisation of this analogue with IPNS provides firm structural evidence for the utility of such cyclobutanone derivatives as hydrolytically stable analogues of bicyclic beta-lactams.
Subject(s)
Cyclobutanes/chemistry , Oxidoreductases/chemistry , Penicillins/chemistry , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Penicillins/chemical synthesis , StereoisomerismABSTRACT
Isopenicillin N synthase (IPNS), a non-heme iron oxidase central to penicillin and cephalosporin biosynthesis, catalyzes an energetically demanding chemical transformation to produce isopenicillin N from the tripeptide delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-valine (ACV). We describe the synthesis of two cyclopropyl-containing tripeptide analogues, delta-(l-alpha-aminoadipoyl)-l-cysteinyl-beta-methyl-d-cyclopropylglycine and delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-cyclopropylglycine, designed as probes for the mechanism of IPNS. We have solved the X-ray crystal structures of these substrates in complex with IPNS and propose a revised mechanism for the IPNS-mediated turnover of these compounds. Relative to the previously determined IPNS-Fe(II)-ACV structure, key differences exist in substrate orientation and water occupancy, which allow for an explanation of the differences in reactivity of these substrates.
Subject(s)
Oligopeptides/metabolism , Oxidoreductases/chemistry , Aspergillus nidulans/enzymology , Crystallization , Crystallography, X-Ray , Models, Molecular , Oligopeptides/chemical synthesis , Oxidoreductases/metabolismABSTRACT
A close examination of Mehta and Kundu's synthesis of an analogue of spiculoic acid A revealed discrepancies between their proposed structure and corresponding data. A revised structure is proposed for Mehta and Kundu's analogue after a careful analysis of their key synthetic transformations and published data. [reaction: see text].