• Each module consists of a minimum of a Ketosynthase (KS), an Acyltransferase (AT), and an Acyl carrier protein (ACP) but may also contain a Ketoreductase (KR), Dehydrotase (DH), and Enoyl Reductase (ER) for additional reduction reactions. (wikipedia.org)
  • The TYLS system also contains a loading module consisting of a ketosynthase‐like decarboxylase domain, an acyltransferase, and acyl carrier protein. (wikipedia.org)
  • The two FabA-like DH domains in the E. huxleyi PUFA synthase function as 3-hydroxyacyl-acyl carrier protein dehydratase in E. coli . (biomedcentral.com)
  • In contrast to their cis -acyltransferase (AT) counterparts, trans -AT PKSs rely on stand-alone AT domains to load extender units onto acyl carrier protein (ACP) domains embedded in the core PKS machinery. (bvsalud.org)
  • The architecture of a full-length PKS module from the pikromycin pathway of Streptomyces venezuelae creates a reaction chamber for the intramodule acyl carrier protein (ACP) domain that carries building blocks and intermediates between acyltransferase, ketosynthase and ketoreductase active sites (see accompanying paper). (inra.fr)
  • Polyketide synthases (PKSs) are multi-domain enzymatic assembly lines that biosynthesise a wide selection of bioactive natural products from simple building blocks. (bvsalud.org)
  • Our results advance the currently incomplete understanding of polyketide biosynthesis by trans -AT PKSs, and provide foundations for future bioengineering efforts. (bvsalud.org)
  • Modular polyketide synthases (PKSs) are biosynthetic assembly lines that construct structurally diverse natural products with wide-ranging applications in medicine and agriculture. (bvsalud.org)
  • Their biosynthetic machinery, represented by type I polyketide synthases (PKSs), has an architecture in which successive modules catalyse two-carbon linear extensions and keto-group processing reactions on intermediates covalently tethered to carrier domains. (inra.fr)
  • Polyunsaturated fatty acid (PUFA) synthase is a multi-domain mega-enzyme that effectively synthesizes a series of PUFAs in marine microorganisms. (biomedcentral.com)
  • The polyketide synthase (PKS) mega-enzyme assembly line uses a modular architecture to synthesize diverse and bioactive natural products that often constitute the core structures or complete chemical entities for many clinically approved therapeutic agents. (inra.fr)
  • Biosynthesis reactions that interchange the KR domain from TYLS with the KR domain from DEBS lead to products with different stereochemistry. (wikipedia.org)
  • A dual role for a polyketide synthase in dynemicin enediyne and anthraquinone biosynthesis. (nih.gov)
  • Hence, introduction of DH domains controlling the dehydration process of fatty acid biosynthesis in plants might offer a new strategy to increase oil production in oilseed plants. (biomedcentral.com)
  • Trans -AT PKS gene clusters also encode acyl hydrolase (AH) domains, which are predicted to share the overall fold of AT domains, but hydrolyse aberrant acyl chains from ACP domains, thus ensuring efficient polyketide biosynthesis. (bvsalud.org)
  • The biosynthesis of these compounds is based on ordered assembly lines of multi-domain modules, each extending and modifying a specific chain-elongation intermediate before transfer to the next module for further processing. (inra.fr)
  • Periplasmic glucan biosynthesis protein [Interproscan]. (ntu.edu.sg)
  • The dehydratase (DH) domain of a PUFA synthase plays a crucial role in double bond positioning in fatty acids. (biomedcentral.com)
  • Various mechanisms contribute to structural diversification during PKS-mediated chain assembly, including dehydratase (DH) domain-mediated elimination of water from R and S-configured 3-hydroxy-thioesters to introduce E- and Z-configured carbon-carbon double bonds, respectively. (bvsalud.org)
  • Here we report the discovery of a DH domain variant that catalyzes the sequential elimination of two molecules of water from a (3R, 5S)-3,5-dihydroxy thioester during polyketide chain assembly, introducing a conjugated E,Z-diene into various modular PKS products. (bvsalud.org)
  • Modular polyketide synthases (PKS) produce a vast array of bioactive molecules that are the basis of many highly valued pharmaceuticals. (inra.fr)
  • They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. (nih.gov)
  • A team from Lilly Research Laboratories designed a hybrid tylactone/platenolide synthase that was able to accept the propionate substrate from the TYLS loading module instead of acetate, the natural precursor in the platenolide synthase system. (wikipedia.org)
  • However, the substrate specificity and functions of the FabA-like DH domains from distinct species remain unclear. (biomedcentral.com)
  • How such domains specifically target short acyl chains, in particular acetyl groups, tethered as thioesters to the substrate-shuttling ACP domains, with hydrolytic rather than acyl transfer activity, has remained unclear. (bvsalud.org)
  • This study reveals for the first time, to our knowledge, the structural basis for both intramodule and intermodule substrate transfer in polyketide synthases, and establishes a new model for molecular dissection of these multifunctional enzyme systems. (inra.fr)
  • The ACP domain is differentially and precisely positioned after polyketide chain substrate loading on the active site of the ketosynthase, after extension to the beta-keto intermediate, and after beta-hydroxy product generation. (inra.fr)
  • The unexpected module architecture revealed a striking evolutionary divergence of the polyketide synthase compared to its metazoan fatty acid synthase homolog, as well as remarkable conformational rearrangements dependent on its biochemical state during the full catalytic cycle. (inra.fr)
  • A single reaction chamber provides access to all catalytic sites for the intramodule carrier domain. (inra.fr)
  • Because polyketide synthases catalyze stereospecific reactions, there is interest in engineering new molecules via PKS engineering. (wikipedia.org)
  • For example, in the figure showing trypanothione reductase from the human protozoan parasite Trypanosoma cruzi, two molecules of an inhibitor called quinacrine mustard are bound in its active site. (pdgfrsignals.com)
  • Especially in the drug discovery field, knowledge of how small molecules associate with proteins plays a fundamental role in understanding how drugs or metabolites can affect cells, tissues, and human metabolism. (uni-freiburg.de)
  • protein_coding" "AAC73572","dnaX","Escherichia coli","DNA polymerase III/DNA elongation factor III, tau and gamma subunits [Ensembl]. (ntu.edu.sg)
  • DNA polymerase III subunits gamma and tau domain III, DNA polymerase III subunits tau domain IV DnaB-binding, DNA polymerase III tau subunit V interacting with alpha [Interproscan]. (ntu.edu.sg)
  • Therefore, the current study, sought to define the functions of these DH domains ( Eh DHs), by cloning and overexpressing the genes encoding FabA-like Eh DHs in Escherichia coli ( E. coli ) and Arabidopsis thaliana ( A. thaliana ). (biomedcentral.com)
  • protein_coding" "AAC73204","ftsQ","Escherichia coli","divisome assembly protein, membrane anchored protein involved in growth of wall at septum [Ensembl]. (ntu.edu.sg)
  • protein_coding" "AAC73303","nlpE","Escherichia coli","lipoprotein involved with copper homeostasis and adhesion [Ensembl]. (ntu.edu.sg)
  • protein_coding" "AAC73733","dacA","Escherichia coli","D-alanyl-D-alanine carboxypeptidase (penicillin-binding protein 5) [Ensembl]. (ntu.edu.sg)
  • protein_coding" "AAC73904","mntR","Escherichia coli","Mn(2+)-responsive manganese regulon transcriptional regulator [Ensembl]. (ntu.edu.sg)
  • protein_coding" "AAC73976","ftsK","Escherichia coli","DNA translocase at septal ring sorting daughter chromsomes [Ensembl]. (ntu.edu.sg)
  • protein_coding" "AAC74007","cmoM","Escherichia coli","putative S-adenosyl-L-methionine-dependent methyltransferase [Ensembl]. (ntu.edu.sg)
  • protein_coding" "AAC74207","potD","Escherichia coli","spermidine/putrescine ABC transporter periplasmic binding protein [Ensembl]. (ntu.edu.sg)
  • Polyketide natural products constitute a broad class of compounds with diverse structural features and biological activities. (inra.fr)
  • A structural dendrogram of the actinobacteriophage major capsid proteins provides important structural insights into the evolution of capsid stability. (nih.gov)
  • First, the pocket, conservation, structural and energy profiles, and physicochemical properties of (non)covalently bound cysteines were collected from both protein sequences and 3D structures of protein-ligand complexes. (uni-freiburg.de)
  • Other efforts have engineered systems by expressing a chalcomycin synthase genes along with the TYLS system. (wikipedia.org)
  • Meanwhile, overexpression of FabA-like Eh DH 1 and Eh DH 2 domains increased the production of unsaturated fatty acids (UFAs) in recombinant E. coli by 43.5-32.9%, respectively. (biomedcentral.com)
  • The expression of these domains in E. coli and A. thaliana can alter the fatty acid profile in E. coli and increase the seed lipid content and germination rate in A. thaliana . (biomedcentral.com)
  • Here we used electron cryo-microscopy to determine sub-nanometre-resolution three-dimensional reconstructions of a full-length PKS module from the bacterium Streptomyces venezuelae that revealed an unexpectedly different architecture compared to the homologous dimeric mammalian fatty acid synthase. (inra.fr)
  • TYLS is composed of five large multi-functional proteins, TylGI-V. Each protein contains either one or two modules. (wikipedia.org)
  • The first 3D structures of a full polyketide synthase module in different functional states were obtained recently by electron cryo-microscopy. (inra.fr)
  • We show that the reaction proceeds via a (2E, 5S)-2-enoyl-5-hydroxy-thioester intermediate and involves an additional universally conserved histidine residue that is absent from the active site of most conventional DH domains. (bvsalud.org)
  • In contrast, the carrier from the preceding module uses a separate entrance outside the reaction chamber to deliver the upstream polyketide intermediate for subsequent extension and modification. (inra.fr)
  • Conformational changes linked to ADP release from human cardiac myosin bound to actin-tropomyosin. (nih.gov)
  • Conformational switching and flexibility in cobalamin-dependent methionine synthase studied by small-angle X-ray scattering and cryo-electron microscopy. (nih.gov)
  • Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain. (nih.gov)
  • bipartite and monopartite types consist of different genome organization. (preprints.org)
  • Site-directed mutagenesis analysis confirmed the authenticity of active-site residues in these domains. (biomedcentral.com)
  • Cryo-EM structure of Shiga toxin 2 in complex with the native ribosomal P-stalk reveals residues involved in the binding interaction. (nih.gov)
  • Here we present a novel pan-BDi with micromolar affinities to various BDs, and nanomolar affinities to representatives of BD families I, II (Bromodomain and Extra-Terminal Domain (BET) family), III, and IV. (uni-freiburg.de)
  • NlpE N-terminal domain, NlpE C-terminal OB domain [Interproscan]. (ntu.edu.sg)
  • SurA N-terminal domain, PPIC-type PPIASE domain [Interproscan]. (ntu.edu.sg)
  • DEAD/DEAH box helicase, Helicase conserved C-terminal domain [Interproscan]. (ntu.edu.sg)
  • AAA C-terminal domain, MgsA AAA+ ATPase C terminal, ATPase family associated with various cellular activities (AAA) [Interproscan]. (ntu.edu.sg)
  • S1 RNA binding domain, Ribonuclease E/G family, Polyribonucleotide phosphorylase C terminal [Interproscan]. (ntu.edu.sg)
  • In this review, we summarize recent progress and give an overview of the cellular process of cellulase production in T. reesei , including the carbon source-dependent cellulase induction, complicated transcriptional regulation network, and efficient protein assembly and trafficking. (springeropen.com)
  • In this article, based on current studies, the cellular process of cellulase production in T. reesei , consisting of carbon source-dependent cellulase induction, complicated transcriptional regulation network, and efficient protein assembly and trafficking, are broadly reviewed, giving new perspectives for further exploration and engineering. (springeropen.com)
  • Combining our experimental findings with molecular dynamics simulations allowed for the production of a data-driven model of an AH:ACP domain complex. (bvsalud.org)
  • In the aerobic pathway common in eukaryotes VLCPUFA synthesis is catalyzed by two types of enzymes. (biomedcentral.com)
  • Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes HN - 2005 BX - Signal Transducing Adaptor Proteins MH - Adrenogenital Syndrome UI - D047808 MN - C19.391.775.129 MS - Abnormal SEXUAL DIFFERENTIATION caused by disorders of the GONADS or the ADRENAL GLANDS, such as CONGENITAL ADRENAL HYPERPLASIA and ADRENAL CORTEX NEOPLASMS. (nih.gov)
  • The loading module contains a ketosynthase‐like decarboxylase domain (KSQ) that decarboxylates the methylmalonyl-CoA loaded onto the ACP via the AT. (wikipedia.org)
  • The DH then catalyzes dehydration resulting in an ACP bound triketide. (wikipedia.org)
  • The AT of module 3 loads malonyl-CoA onto the ACP, followed by a Claisen condensation with the bound triketide, a KR-mediated reduction and dehydration catalyzed by the DH. (wikipedia.org)
  • In particular, two types of DH domains participate in the dehydration process for double bond introduction. (biomedcentral.com)
  • The domains of TYLS have similar activity domains to those found in other Type I polyketide synthase such as 6-Deoxyerythronolide B synthase (DEBS). (wikipedia.org)
  • To answer these questions, we solved the first structure of an AH domain and performed structure-guided activity assays on active site variants. (bvsalud.org)
  • As glycogen accretion occurs, glycogen synthase becomes phosphorylated, reducing glycogen synthase activity. (pdgfrsignals.com)
  • However, since module 4 contains an inactive KR domain, the β-ketone condensation product is maintained. (wikipedia.org)
  • Our results offer key insights into chain length control and selection against coenzyme A-tethered substrates, and clarify how the interaction interface between AH and ACP domains contributes to recognition of cognate and non-cognate ACP domains. (bvsalud.org)
  • It is anticipated that HyperCys will be an effective tool for discovering new potential reactive cysteines in a wide range of nucleophilic proteins and will provide an important contribution to the design of targeted covalent inhibitors with high potency and selectivity. (uni-freiburg.de)
  • AN - coordinate IM with SKIN NEOPLASMS (IM) HN - 2005 BX - Acanthoma, Clear Cell MH - Adaptor Proteins, Signal Transducing UI - D048868 MN - D12.644.360.24 MN - D12.776.157.57 MN - D12.776.476.24 MS - A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. (nih.gov)
  • Module 1 extends the propionate by loading methylmalonate onto the ACP and catalyzing a Claisen condensation with the propionate bound to the KS. (wikipedia.org)
  • Module 2 loads the ACP with methylmalonate via the module 2 AT followed by a Claisen condensation with the diketide bound to the KS and a KR-mediated reduction, a reaction sequence similar to that of module 1. (wikipedia.org)
  • The triketide is then passed via the ACP of module 2 to the KS of module 3 on TylGII via docking domains. (wikipedia.org)
  • The tetraketide is then passed to module 4 on TylGIII paired docking domains. (wikipedia.org)
  • The AT of module 4 loads methylmalonyl-CoA onto the module 4 ACP and catalyzes a Claisen condensation with the bound tetraketide. (wikipedia.org)
  • The hexaketide product of TylGIII is passed to the KS on module 6 on TylGIV via docking domain interactions. (wikipedia.org)
  • Module 6 loads methylmalonyl CoA onto the ACP and catalyzes a Claisen condensation followed by a β-keto reduction by the KR domain. (wikipedia.org)
  • The heptaketide product is then passed to the KS on module 7 on TylGV via paired docking domains on TylGIV. (wikipedia.org)
  • Other studies have elucidated the stereospecificity of the DEBS DH domain by co-incubating the DEBS DH domain with the TYLS KR from module 1 and comparing the product to that produced by the DEBS system. (wikipedia.org)
  • Sequencing results of the coccolithophore Emiliania huxleyi ( E. huxleyi, Eh ) indicated that this species contains a PUFA synthase with multiple DH domains. (biomedcentral.com)
  • In addition to increasing GLUT4 concentration at the cell membrane, Akt deactivates glycogen synthase kinase 3 (GSK-3), which learn more allows activation, or dephosphorylation, of glycogen synthase [37-39]. (pdgfrsignals.com)
  • POTRA domain, Cell division protein FtsQ [Interproscan]. (ntu.edu.sg)
  • Leucyl-tRNA synthetase, tRNA synthetases class I (I, Anticodon-binding domain of tRNA [Interproscan]. (ntu.edu.sg)
  • In this cohort study of 71?659 Medicare claims from 1732 oncology practices, most practices adopted immunotherapy within 2 years of FDA approval, but adoption was not equal across practice types: adoption was lower at rural vs urban practices and small vs large practices. (cdc.gov)
  • Ftsk gamma domain, FtsK alpha domain, FtsK/SpoIIIE family, 4TM region of DNA translocase FtsK/SpoIIIE [Interproscan]. (ntu.edu.sg)