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Tumor budding (TB) and poorly differentiated clusters (PDCs) are well-established prognostic factors in various cancers. This study aimed to assess the independent prognostic role of these markers in endometrial carcinomas. Retrospective analysis of endometrial carcinoma resection specimens by examining traditional histologic prognostic parameters. TB and PDC were observed at 20× magnification in ten fields at the invasive front and categorized as present or absent. In addition, a count of ≥5 was stratified as "high." Clinical and follow-up details were extracted from Gynecologic Oncology records. Sixty-five endometrial carcinomas were studied and were predominantly endometrioid (n=47, 72.3%). TB was identified in 52.3% of cases, with high TB observed in 38.5%. PDC was evident in 44.6%, with high PDC seen in 29.2%. Associations were significant between the presence of TB/high TB and higher tumor grade (P < 0.001), deep myometrial invasion (P = 0.006/P = 0.002), diffuse pattern of invasion (P = 0.007/P = 0.03), microcystic elongated and fragmented pattern (P < 0.001), lymphovascular space invasion, lymph node metastasis (P=<0.001) and International Federation of Gynecology and Obstetrics stage (P = 0.000/P = 0.002). PDC/high PDC showed similar associations, and, in addition, with nonendometrioid histologic type (P = 0.02) and tumor location in a lower uterine segment (high PDC, P = 0.009). After adjusting for other significant parameters, both high TB (P = 0.03) and high PDC (P = 0.031) emerged as independent prognostic parameters for lymphovascular space invasion or Lymph node metastasis. No recorded deaths or significant events occurred, precluding commentary on overall survival status. High TB and PDC are independent predictors of Lymph node metastasis in endometrial carcinomas. Their association with the microcystic elongated and fragmented pattern makes them histologic predictors of epithelial-mesenchymal transition. Their simple application underscores their potential as valuable additional prognostic indicators for endometrial carcinomas.
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Epoxide hydrolases (EHs) are a group of ubiquitous enzymes that catalyze hydrolysis of chemically reactive epoxides to yield corresponding dihydrodiols. Despite extensive studies on EHs from different clades, generic rules governing their substrate specificity determinants have remained elusive. Here, we present structural, biochemical and molecular dynamics simulation studies on MiEH2, a plant epoxide hydrolase from Mangifera indica. Comparative structure-function analysis of nine homologs of MiEH2, which include a few AlphaFold structural models, show that the two conserved tyrosines (MiEH2Y152 and MiEH2Y232) from the lid domain dissect substrate binding tunnel into two halves, forming substrate-binding-pocket one (BP1) and two (BP2). This compartmentalization offers diverse binding modes to their substrates, as exemplified by the binding of smaller aromatic substrates, such as styrene oxide (SO). Docking and molecular dynamics simulations reveal that the linear epoxy fatty acid substrates predominantly occupy BP1, while the aromatic substrates can bind to either BP1 or BP2. Furthermore, SO preferentially binds to BP2, by stacking against catalytically important histidine (MiEH2H297) with the conserved lid tyrosines engaging its epoxide oxygen. Residue (MiEH2L263) next to the catalytic aspartate (MiEH2D262) modulates substrate binding modes. Thus, the divergent binding modes correlate with the differential affinities of the EHs for their substrates. Furthermore, long-range dynamical coupling between the lid and core domains critically influences substrate enantioselectivity in plant EHs.
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The effectiveness of Oil Pulling Therapy (OPT) with coconut (CO) and sesame oil (SO) on gingivitis patients is of interest. Forty patients were randomly distributed into group A and B for CO and SO respectively. Participants of group A were explained in detail about the OPT with CO and group B with SO along with their routine oral hygiene practice for 30 days. The mean plaque index of CO and SO reduced from 1.5 to 1.32 and 1.65 to 1.36 (p<0.05) respectively after 30 days. The mean gingival index of CO and SO declined from 1.12 to 0.9 and 1.1 to 0.81 respectively after 30 days (p<0.05) compared to initial scores. The mean no. of colonies in the case of CO and SO declined from 35.8 x 103 to 32.4 x 103 and 6.8 x 103 to 34.6 x 103 after 30 days (p<0.05). OPT reduced plaque and gingivitis, according to the results of one month. Hence, we must increase awareness about oil pulling, as this home therapy can prevent gingival diseases in countries with limited resources like ours.
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A number of small molecule and protein therapeutic candidates have been developed in the last four years against SARS-CoV-2 spike. However, there are hardly a few molecules that have advanced through the subsequent discovery steps to eventually work as a therapeutic agent. This is majorly because of the hurdles in determining the affinity of potential therapeutics with live SARS-CoV-2 virus. Furthermore, affinity determined for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, at times, fails to mimic physiological conditions of the host-virus interaction. To bridge this gap between in vitro and in vivo methods of therapeutic agent screening, we report an improved screening protocol for therapeutic candidates using SARS-CoV-2 virus like particles (VLPs). To minimise the interference from the bulkier reporters like GPF in the affinity studies, a smaller hemagglutinin (HA) tag has been fused to one of the proteins of VLP. This HA tag serves as readout, when probed with fluorescent anti-HA antibodies. Outcome of this study sheds light on the lesser known virus neutralisation capabilities of AM type miniprotein mimics. Further, to assess the stability of SARS-CoV-2 spike - miniprotein complex, we have performed molecular dynamic simulations on the membrane embedded protein complex. Simulation results reveal extremely stable intermolecular interactions between RBD and one of the AM type miniproteins, AM1. Furthermore, we discovered a robust network of intramolecular interactions that help stabilise AM1. Findings from our in vitro and in silico experiments concurrently highlight advantages and capabilities of mimic based miniprotein therapeutics.
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SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Humanos , COVID-19/virologia , COVID-19/imunologia , Ligação Proteica , Vírion/metabolismo , Antivirais/farmacologia , Antivirais/química , Células HEK293RESUMO
The Wnt-planar cell polarity (Wnt-PCP) pathway is crucial in establishing cell polarity during development and tissue homoeostasis. This pathway is found to be dysregulated in many pathological conditions, including cancer and autoimmune disorders. The central event in Wnt-PCP pathway is the activation of Weak-similarity guanine nucleotide exchange factor (WGEF) by the adapter protein Dishevelled (Dvl). The PDZ domain of Dishevelled2 (Dvl2PDZ) binds and activates WGEF by releasing it from its autoinhibitory state. However, the actual Dvl2PDZ binding site of WGEF and the consequent activation mechanism of the GEF have remained elusive. Using biochemical and molecular dynamics studies, we show that a unique "internal-PDZ binding motif" (IPM) of WGEF mediates the WGEF-Dvl2PDZ interaction to activate the GEF. The residues at P2, P0, P-2 and P-3 positions of IPM play an important role in stabilizing the WGEFpep-Dvl2PDZ interaction. Furthermore, MD simulations of modelled Dvl2PDZ-WGEFIPM peptide complexes suggest that WGEF-Dvl2PDZ interaction may differ from the reported Dvl2PDZ-IPM interactions. Additionally, the apo structure of human Dvl2PDZ shows conformational dynamics different from its IPM peptide bound state, suggesting an induced fit mechanism for the Dvl2PDZ-peptide interaction. The current study provides a model for Dvl2 induced activation of WGEF.
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Proteínas Desgrenhadas , Fatores de Troca do Nucleotídeo Guanina , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas Desgrenhadas/metabolismo , Proteínas Desgrenhadas/química , Proteínas Desgrenhadas/genética , Humanos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fatores de Troca do Nucleotídeo Guanina/química , Fatores de Troca do Nucleotídeo Guanina/genética , Domínios PDZ , Motivos de Aminoácidos , Via de Sinalização Wnt , Peptídeos/metabolismo , Peptídeos/química , Sítios de Ligação , Proteínas dos Microfilamentos , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
The Ras superfamily of GTPases regulate critical cellular processes by shuttling between GTP-bound ON and GDP-bound OFF states. This switching mechanism is attributed to the conformational changes in two loops, SWI and SWII, upon GTP binding and hydrolysis. Since these conformational changes vary across the Ras superfamily, there is no generic parameter to define their functional states. A unique wavelet coherence (WC) analysis-based approach developed here shows that the structural changes in switch regions could be mapped onto the wavelet coherence phase couplings (WPCs). Thus, WPCs could serve as unique parameters to define their functional states. Disentanglement of WPCs in oncogenic GTPases shows how breakdown of structural allostery leads to their aberrant function. These observations stand out even for simulated ensemble of switch region conformers. Overall, for the first time, we show that WPCs could unravel the latent structural deviations in Ras proteins to decode their universal switching mechanism.
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Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 µM, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 µM against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Antituberculosos/química , Silício/farmacologia , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico , Proteínas de Bactérias/metabolismoRESUMO
Ovastacin (ASTL), a zinc metalloprotease, is released from a fertilized egg during exocytosis of cortical granules which occurs minutes after the sperm and egg fuse. ASTL cleaves ZP2, one of the four primary glycoproteins of human zona pellucida, and this cleavage prevents polyspermy, causes zona pellucida hardening, and also protects the pre-implantation embryo. Any perturbation in the activity of ASTL can thus disturb this process and may lead to infertility without changing the gross morphology of the oocyte. A small amount of ASTL is also released by unfertilized oocytes but its catalytic activity is absent as it is bound by its inhibitor, Fetuin-B (FETUB). Pre-mature release of ASTL when FETUB is absent also causes infertility. To identify and understand the structural and functional effects of deleterious SNPs of ASTL on its interaction with ZP2 and FETUB and hence on fertility, a total of 4,748 SNPs from the dbSNP database were evaluated using a variety of in silico tools. All of the 40 shortlisted nsSNPs were present in the catalytic domain of the protein. Comparison of the wild type with mutants using MutPred2 suggests an alteration in the catalytic activity/zinc binding site in many SNPs. Docking studies show the involvement of hydrophobic interactions and H bonding between ASTL and ZP2 and also between ASTL and FETUB. Four positions in ASTL involved in the hydrophobic interactions (P105 and D200 between ASTL and ZP2; D198 and L278 between ASTL and FETUB) and 5 in H bonding (E75 and R159 between ASTL and ZP2; and K93, R159, and C281 between ASTL and FETUB) have SNP's associated with them validating their importance. Interestingly, a cluster of multiple SNPs was found in the motif 198DRD200, which is also a well-conserved region among several species. Statistical Coupling Analysis (SCA) suggested that the deleterious SNPs were present in the functionally important amino acid positions of ASTL and are evolutionarily coupled. Thus, these results attempt to identify the regions in ASTL, mutations in which can affect its binding with ZP2 or FETUB and cause female infertility.
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EngA is an essential and unique bacterial GTPase involved in ribosome biogenesis. The essentiality and species-specific variations among EngA homologues make the protein a potential target for future drug development. In this aspect, it is important to understand the variations of EngA among probiotic organisms and non-probiotic bacteria to understand species specificity. The search for variations among EngA homologues revealed a unique variant, exclusively found in Bifidobacterium and a few Actinobacteria species. Bifidobacterium possesses a multifunctional fusion protein, wherein EngA is fused with an N-terminal CMK (Cytidylate Monophosphate Kinase) domain. The resulting protein is therefore a large (70kDa size) with 3 consecutive P-loops and a 50 amino acid long linker connecting the EngA and CMK domains. EngA is known to regulate ribosome biogenesis via nucleotide-dependent conformational changes. The additional domain may introduce further intricate regulation in ribosome biogenesis or participate in newer biological processes. This study is the first attempt to characterise this novel class of bacterial EngA found in the Genus of Bifidobacteria.
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Protein function is encoded in its sequence, manifested in its three-dimensional structure, and facilitated by its dynamics. Studies have suggested that protein structures with higher sequence similarity could have more similar patterns of dynamics. However, such studies of protein dynamics within and across protein families typically rely on coarse-grained models, or approximate metrics like crystallographic B-factors. This study uses µs scale molecular dynamics (MD) simulations to explore the conservation of dynamics among homologs of â¼50 kDa N-terminal module of Spt16 (Spt16N). Spt16N from Saccharomyces cerevisiae (Sc-Spt16N) and three of its homologs with 30-40% sequence identities were available in the PDB. To make our data-set more comprehensive, the crystal structure of an additional homolog (62% sequence identity with Sc-Spt16N) was solved at 1.7 Å resolution. Cumulative MD simulations of 6 µs were carried out on these Spt16N structures and on two additional protein structures with varying degrees of similarity to it. The simulations revealed that correlation in patterns of backbone fluctuations vary linearly with sequence identity. This trend could not be inferred using crystallographic B-factors. Further, normal mode analysis suggested a similar pattern of inter-domain (inter-lobe) motions not only among Spt16N homologs, but also in the M24 peptidase structure. On the other hand, MD simulation results highlighted conserved motions that were found unique for Spt16N protein, this along with electrostatics trends shed light on functional aspects of Spt16N.Communicated by Ramaswamy H. Sarma.
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Simulação de Dinâmica Molecular , Proteínas , Proteínas/química , Domínios Proteicos , Peptídeo Hidrolases , Conformação ProteicaRESUMO
The directed Rh(III)-catalyzed cross dehydrogenative coupling of the pyrazole unit of the GBT-440 scaffold has been explored with simple as well as conjugated olefins to synthesize post-functionalized GBT-440 analogues. The screening of these synthesized compounds for improving the oxygen binding efficiency of the hemoglobin isolated from the sickled red blood cells revealed that some of these compounds are as good as GBT-440.
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Alcenos , Benzaldeídos , Alcenos/química , Catálise , PirazóisRESUMO
Dedicator of cytokinesis (DOCK) family of guanine nucleotide exchange factors (GEFs) activate two members of Rho family GTPases, Rac1/Cdc42, to exert diverse cellular processes, including cell migration. As DOCK GEFs have been critically implicated in tumour cell migration, understanding their function and specificity is imperative for designing anti-metastatic drugs. Based on their GTPase specificity they have been classified as Rac, Cdc42 and dual specific GEFs. Despite extensive structural studies, the factors that determine GTPase specificity of DOCK GEFs have remained elusive. Here, we show that subtle dynamical coupling between GEF and GTPase structures modulate the binding interface to generate mutual specificity. To cluster the dynamically coupled residues in GEF-GTPase complexes a novel intra-residue backbone-torsion-angles based mutual information (TMI) technique was employed. TMI was calculated from 4500 trajectories obtained from a total of 4.5µs molecular dynamics simulations performed on members of all the three clades of DOCK GEFs. The obtained clusters suggest a specificity generation mechanism that involves optimization of the binding pocket for the crucial divergent residue at the 56th position of Rac/Cdc42 (FCdc42/WRac1). These clusters encompass five residues from the structural segment lobe C - α10 helix of the DOCK proteins and functional SWI region of GTPase, which induce orchestrated structural modulations to generate the specificity. Even the conserved residues from SWI region are seen to augment the specificity defining dynamical rearrangements. Furthermore, the proposed dynamical GTPase- DOCK GEF specificity model was verified using mutagenesis studies on Rac1 and dual GTPase specific Dock2 and Dock6, respectively. Thus the current study provides the generic substrate specificity determinants of DOCK GEFs, which are not apparent from the conventional structural analysis.
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Citocinese , Fatores de Troca do Nucleotídeo Guanina , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Mutagênese , Especificidade por SubstratoRESUMO
Cell migration, a crucial step in numerous biological processes, is tightly regulated in space and time. Cells employ Rho GTPases, primarily Rho, Rac, and Cdc42, to regulate their motility. Like other small G proteins, Rho GTPases function as biomolecular switches in regulating cell migration by operating between GDP bound 'OFF' and GTP bound 'ON' states. Guanine nucleotide exchange factors (GEFs) catalyse the shuttling of GTPases from OFF to ON state. G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors that are involved in many signalling phenomena including cell survival and cell migration events. In this review, we summarize signalling mechanisms, involving GPCRs, leading to the activation of RhoGEFs. GPCRs exhibit diverse GEF activation modes that include the interaction of heterotrimeric G protein subunits with different domains of GEFs, phosphorylation, protein-protein interaction, protein-lipid interaction, and/or a combination of these processes.
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Receptores Acoplados a Proteínas G , Proteínas rho de Ligação ao GTP , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Leukoencephalopathy, cerebral calcifications, and cysts (LCC) form a very rare association which is named as "Labrune syndrome" after Labrune who reported the first case in 1996. To the best of our knowledge only eight to 10 cases have been reported in literature to date. We report a case of a 26-year-old male with onset of neurological symptoms in late adolescence (at 19 years of age) and presented with complains of continued seizures for 7 years, giddiness with imbalance, and slowly progressive motor symptoms. MRI brain revealed multiple calcifications in bilateral basal ganglia, cerebral white matter, multiple cystic lesions in the supratentorial white matter, and abnormal diffused bilateral white matter T2 hyperintensity suggesting leukoencephalopathy. Histopathological evaluation revealed prominent congested blood vessels suggestive of angiomatous changes and cystic areas suggestive of secondary gliosis.
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De novo design of mini-proteins (4-12 kDa) has recently been shown to produce new candidates for protein therapeutics. They are temperature stable molecules that bind to the drug target with high affinity for inhibiting its interactions. The development of mini-protein binders requires laboratory screening of tens of thousands of molecules for effective target binding. In this study we trained machine learning classifiers which can distinguish, with 90% accuracy and 80% precision, mini-protein binders from non-binding molecules designed for a particular target; this significantly reduces the number of mini protein candidates for experimental screening. Further, on the basis of our results we propose a multi-stage protocol where a small dataset (few hundred experimentally verified target-specific mini-proteins) can be used to train classifiers for improving the efficiency of mini-protein design for any specific target.
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Aprendizado de Máquina , Proteínas/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Ligantes , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Asrij/OCIAD1 is a scaffold transmembrane protein belonging to the Ovarian Carcinoma Immunoreactive Antigen Domain containing protein family. In Drosophila and mouse models, Asrij localizes at the endosomal and mitochondrial membrane and is shown to regulate the stemness of hematopoietic stem cells. Interaction of Asrij with ADP Ribosylation Factor 1 (Arf1) is shown to be crucial for hematopoietic niche function and prohemocyte maintenance. Here, we report the heterologous expression, standardization of detergents and purification methodologies for crystallization of Asrij/OCIAD1. To probe the activity of bacterially expressed Asrij, we developed a protein complementation assay and conclusively show that Asrij and Arf1 physically interact. Further, we find that sophorolipids improve the solubility and monodispersibility of Asrij. Hence, we propose that sophorolipids could be novel additives for stabilization of membrane proteins. To our knowledge, this is the first study detailing methodology for the production and crystallization of a heterologously expressed scaffold membrane protein and will be widely applicable to understand membrane protein structure and function.
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Proteínas de Membrana/química , Animais , Cristalização , Proteínas de Membrana/genética , CamundongosRESUMO
Sesquiterpene synthases catalyse cyclisation of farnesyl pyrophosphate to produce diverse sesquiterpenes. Despite utilising the same substrate and exhibiting significant sequence and structural homology, these enzymes form different products. Previous efforts were based on identifying the effect of divergent residues present at the catalytic binding pocket on the product specificity of these enzymes. However, the rationales deduced for the product specificity from these studies were not generic enough to be applicable to other phylogenetically distant members of this family. To address this problem, we have developed a novel approach combining sequence, structural and dynamical information of plant sesquiterpene synthases (SSQs) to predict product modulating residues (PMRs). We tested this approach on the SSQs with known PMRs and also on sesquisabinene synthase 1 (SaSQS1), a SSQ from Indian sandalwood. Our results show that the dynamical sectors of SSQs obtained from molecular dynamics simulation and their hydrophobicity and vicinity indices together provide leads for the identification of PMRs. The efficacy of the technique was tested on SaSQS1 using mutagenesis. To the best of our knowledge, this is a first technique of this kind which provides cues on PMRs of SSQs, with divergent phylogenetic relationship.
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Alquil e Aril Transferases/metabolismo , Sesquiterpenos/metabolismo , Alquil e Aril Transferases/química , Sequência de Aminoácidos , Sítios de Ligação , Biocatálise , Evolução Molecular , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Santalum/enzimologia , Sesquiterpenos/químicaRESUMO
Human epidermal growth factors play an important role in ovarian carcinogenesis and are evaluated for prognostic and possible therapeutic roles in high-grade serous ovarian malignancies. The present study was undertaken to evaluate the expression of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) in advanced stage serous carcinoma and their influence on prognosis. The expression of HER2 and EGFR was studied in 59 cases of stage III and IV ovarian serous carcinomas by immunohistochemistry and fluorescent in situ hybridization. Of the 48 interpretable tumors for HER2, 6 tumors (12.5%) were scored as positive, 14 (29%) as equivocal and 28 tumors (58.5%) were negative by immunohistochemistry, while only 2/48 (4%) showed frank amplification by fluorescent in situ hybridization with ≥4 copies per cell. HER2 gene expression measured by quantitative polymerase chain reaction had good positive correlation with both protein expression and gene amplification. Although EGFR expression was seen in 32% of tumors, none of the tumors positive for HER2 protein or gene amplification had co-expression of EGFR indicating mutual exclusivity of their expression. Gene expression of both proteins also confirmed their inverse correlation (Pearsons CC=-0.15, P=0.3). Further there was no influence of protein or gene expression of these markers on the overall survival. In conclusion, HER2 and EGFR are expressed in a small percentage of tumors and the mutual exclusivity of these markers precludes the possibility of dual targeting with anti-HER2 and anti-EGFR therapy in advanced stage high-grade serous ovarian carcinoma.
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Cistadenocarcinoma Seroso/diagnóstico , Neoplasias Ovarianas/diagnóstico , Receptor ErbB-2/metabolismo , Cistadenocarcinoma Seroso/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Prognóstico , Receptor ErbB-2/genética , Análise Serial de TecidosRESUMO
Herein we report the stereochemical revision of peribysins A, B, C, F, and G, guided by enantiospecific total synthesis starting from (+)-nootkatone. Furthermore, we reconfirmed the absolute stereochemistry of peribysin Q. The highlights of the synthesis are enone transposition and kinetic iodination resulting in separation of diastereomers. Our findings coupled with synthetic and biological data previously reported by Danishefsky's group suggest that the original stereochemistries of peribysins A, B, C, F, and G were misassigned.