scholarly journals Algal Neurotoxin Biosynthesis Repurposes the Terpene Cyclase Structural Fold Into an N-prenyltransferase

2020 ◽  
Author(s):  
Jonathan R. Chekan ◽  
Shaun M. K. McKinnie ◽  
Joseph P. Noel ◽  
Bradley S. Moore
Keyword(s):  
Crystal Structure ◽  
Glutamic Acid ◽  
Kainic Acid ◽  
Domoic Acid ◽  
Marine Algae ◽  
Single Amino Acid ◽  
Binding Motif ◽  
Rational Engineering ◽  
New Family ◽  
Terpene Cyclase

AbstractPrenylation is a common biological reaction in all domains of life whereupon prenyl diphosphate donors transfer prenyl groups onto small molecules as well as large proteins. The enzymes that catalyze these biotransformations are structurally distinct from ubiquitous terpene cyclases that instead assemble terpene molecules via intramolecular rearrangements. Herein we report the structure and molecular details of a new family of prenyltransferases from marine algae that repurposes the terpene cyclase structural fold for the N-prenylation of glutamic acid during the biosynthesis of the potent neurochemicals domoic acid and kainic acid. We solved the X-ray crystal structure of the prenyltransferase found in domoic acid biosynthesis, DabA, and show distinct active site binding modifications that remodel the canonical Mg2+-binding motif. We then applied our structural knowledge of DabA and a homologous enzyme from the kainic acid biosynthetic pathway, KabA, to alter their isoprene donor specificities (geranyl versus dimethylallyl diphosphate) by a single amino acid switch. While the diatom DabA and seaweed KabA enzymes share a common evolutionary lineage, they are distinct from all other terpene cyclases, suggesting a very distant ancestor.SignificanceDomoic acid is a neurotoxin produced by marine algae that readily bioaccumulates in shellfish and significantly impacts both human and animal life. The first committed step of the biosynthesis of domoic acid is the N-prenylation of L-glutamic acid by the enzyme DabA. By solving the crystal structure of DabA, we demonstrate that this enzyme has repurposed the common terpene cyclase fold to catalyze an extremely unusual reaction, N-prenylation of an unactivated primary amine. Application of these structural insights enabled rational engineering of two N-prenyltransferase enzymes to accept alternative prenyl donors. Ultimately, these results not only expand the scope of reactions catalyzed by a terpene cyclase family member, but will help inform future domoic acid environmental monitoring efforts.

scholarly journals Algal neurotoxin biosynthesis repurposes the terpene cyclase structural fold into anN-prenyltransferase

2020 ◽  
Vol 117 (23) ◽  
pp. 12799-12805 ◽  
Author(s):  
Jonathan R. Chekan ◽  
Shaun M. K. McKinnie ◽  
Joseph P. Noel ◽  
Bradley S. Moore
Keyword(s):  
Kainic Acid ◽  
Domoic Acid ◽  
Single Amino Acid ◽  
Terpene Synthase ◽  
Binding Motif ◽  
Geranyl Diphosphate ◽  
New Family ◽  
Terpene Cyclase ◽  
Single Amino Acid Change ◽  
Domains Of Life

Prenylation is a common biological reaction in all domains of life wherein prenyl diphosphate donors transfer prenyl groups onto small molecules as well as large proteins. The enzymes that catalyze these reactions are structurally distinct from ubiquitous terpene cyclases that, instead, assemble terpenes via intramolecular rearrangements of a single substrate. Herein, we report the structure and molecular details of a new family of prenyltransferases from marine algae that repurposes the terpene cyclase structural fold for theN-prenylation of glutamic acid during the biosynthesis of the potent neurochemicals domoic acid and kainic acid. We solved the X-ray crystal structure of the prenyltransferase found in domoic acid biosynthesis, DabA, and show distinct active site binding modifications that remodel the canonical magnesium (Mg2+)-binding motif found in terpene cyclases. We then applied our structural knowledge of DabA and a homologous enzyme from the kainic acid biosynthetic pathway, KabA, to reengineer their isoprene donor specificities (geranyl diphosphate [GPP] versus dimethylallyl diphosphate [DMAPP]) with a single amino acid change. While diatom DabA and seaweed KabA enzymes share a common evolutionary lineage, they are distinct from all other terpene cyclases, suggesting a very distant ancestor to the larger terpene synthase family.

Effects of α-kainic acid, domoic acid and their derivatives on a molluscan giant neuron sensitive to β-hydroxy-l-glutamic acid

1984 ◽  
Vol 102 (2) ◽  
pp. 325-332 ◽  
Author(s):  
Hiroshi Takeuchi ◽  
Kazuko Watanabe ◽  
Kyosuke Nomoto ◽  
Yasufumi Ohfune ◽  
Tsunematsu Takemoto
Keyword(s):  
Glutamic Acid ◽  
Kainic Acid ◽  
Domoic Acid ◽  
Giant Neuron

Preparation and crystal structure of new samarium complexes with glutamic acid

2003 ◽  
Vol 660 (1-3) ◽  
pp. 99-106 ◽  
Author(s):  
Julia Torres ◽  
Carlos Kremer ◽  
Helena Pardo ◽  
Leopoldo Suescun ◽  
Alvaro Mombrú ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutamic Acid ◽  
Samarium Complexes

Studies of marine algae in the lesser-known families of the Gigartinales (Rhodophyta). III. The Mychodeaceae and Mychodeophyllaceae

1978 ◽  
Vol 26 (4) ◽  
pp. 515 ◽  
Author(s):  
GT Kraft
Keyword(s):  
Marine Algae ◽  
Adjacent Cell ◽  
Distinctive Pattern ◽  
Supporting Cells ◽  
New Family ◽  
Red Algal ◽  
Single Genus ◽  
Fusion Cell ◽  
Fertile Region ◽  
Axial Development

The endemic Australian red algal families Mychodeaceae Kylin and Mychodeophyllaceae fam. nov. are described and characterized in vegetative and reproductive detail. The Mychodeaceae is composed of the single genus Mychodea and 11 species which are distinguished on habit features and vegetative differences. Plants are uniaxial with a distinctive pattern of axial development, monoecious, zonately tetrasporangiate, procarpic and polycarpogonial. Supporting cells of carpogonial branches function as auxiliary cells which remain unfused to adjacent cells after diploidization and emit numerous gonimoblast filaments towards the centre of the thallus. The gonimoblasts become secondarily pitconnected to gametophytic cells which they lie next to and eventually appear to break up into isolated groups of cells which both initiate additional carposporangial precursors and enlarge directly into carposporangia themselves. Carposporangial initials can form secondary pit-connections to any type of adjacent cell, which results in irregularly branched carposporangial clusters whose cells are frequently attached to sterile gametophytic cells within and around the periphery of the cystocarp. Mature cystocarps consist of a non-ostiolate pericarp and pockets of carposporangia isolated between persistent sterile cells throughout the fertile region. The genera Neurophyllis Zanardini and Ectoclinium J. Agardh are placed in synonymy with Mychodea, and all extra-Australian records of the group are discounted or questioned. A new family, the Mychodeophyllaceae, is created for Mychodeophyllum papillitectum gen. et sp. nov. from Western Australia. Mychodeophyllum shares spermatangial and tetrasporangial features with Mychodea, as well as sexual elements such as polycarpogonial procarps, lack of a fusion cell, and multiple, inwardly growing gonimoblast initials. Gonimoblast filaments develop quite differently from Mychodea, however, and carposporangia form radiating chains around the periphery of a central placenta composed of mixed and secondarily connected gonimoblast and gametophytic filaments. Plants of the genus are also apparently rnultiaxial. The Mychodeaceae and Mychodeophyllaceae appear to be highly specialized in vegetative and carposporophyte structure, and have given rise to no known higher lines of development. It is speculated that both families may represent offshoots from ancestors at a level of carposporophyte complexit) represented by present-day Rhabdoniaceae, Solieriaceae and Rhodophyllidaceae.

WHICH IS THE PROTON-SHUTTLE IN ISOXANTHOPTERIN DEAMINASE? QM/MM MD UNDERSTANDING

2013 ◽  
Vol 12 (08) ◽  
pp. 1341002 ◽  
Author(s):  
XIN ZHANG ◽  
MING LEI
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Proton Transfer ◽  
Glutamic Acid ◽  
Active Site ◽  
Nucleophilic Attack ◽  
Zinc Ions ◽  
Initial Model ◽  
Dynamics Simulations

The deamination process of isoxanthopterin catalyzed by isoxanthopterin deaminase was determined using the combined QM(PM3)/MM molecular dynamics simulations. In this paper, the updated PM3 parameters were employed for zinc ions and the initial model was built up based on the crystal structure. Proton transfer and following steps have been investigated in two paths: Asp336 and His285 serve as the proton shuttle, respectively. Our simulations showed that His285 is more effective than Aap336 in proton transfer for deamination of isoxanthopterin. As hydrogen bonds between the substrate and surrounding residues play a key role in nucleophilic attack, we suggested mutating Thr195 to glutamic acid, which could enhance the hydrogen bonds and help isoxanthopterin get close to the active site. The simulations which change the substrate to pterin 6-carboxylate also performed for comparison. Our results provide reference for understanding of the mechanism of deaminase and for enhancing the deamination rate of isoxanthopterin deaminase.

scholarly journals Crystal Structure of an Aquabirnavirus Particle: Insights into Antigenic Diversity and Virulence Determinism

2009 ◽  
Vol 84 (4) ◽  
pp. 1792-1799 ◽  
Author(s):  
Fasséli Coulibaly ◽  
Christophe Chevalier ◽  
Bernard Delmas ◽  
Félix A. Rey
Keyword(s):  
Crystal Structure ◽  
Three Dimensional ◽  
Salient Feature ◽  
Infectious Pancreatic Necrosis Virus ◽  
Antigenic Determinants ◽  
Binding Motif ◽  
Icosahedral Symmetry ◽  
Fold Axis ◽  
Cell Internalization ◽  
Pancreatic Necrosis Virus

ABSTRACT Infectious pancreatic necrosis virus (IPNV), a pathogen of salmon and trout, imposes a severe toll on the aquaculture and sea farming industries. IPNV belongs to the Aquabirnavirus genus in the Birnaviridae family of bisegmented double-stranded RNA viruses. The virions are nonenveloped with a T=13l icosahedral capsid made by the coat protein VP2, the three-dimensional (3D) organization of which is known in detail for the family prototype, the infectious bursal disease virus (IBDV) of poultry. A salient feature of the birnavirus architecture is the presence of 260 trimeric spikes formed by VP2, projecting radially from the capsid. The spikes carry the principal antigenic sites as well as virulence and cell adaptation determinants. We report here the 3.4-Å resolution crystal structure of a subviral particle (SVP) of IPNV, containing 20 VP2 trimers organized with icosahedral symmetry. We show that, as expected, the SVPs have a very similar organization to the IBDV counterparts, with VP2 exhibiting the same overall 3D fold. However, the spikes are significantly different, displaying a more compact organization with tighter packing about the molecular 3-fold axis. Amino acids controlling virulence and cell culture adaptation cluster differently at the top of the spike, i.e., in a central bowl in IBDV and at the periphery in IPNV. In contrast, the spike base features an exposed groove, conserved across birnavirus genera, which contains an integrin-binding motif. Thus, in addition to revealing the viral antigenic determinants, the structure suggests that birnaviruses interact with different receptors for attachment and for cell internalization during entry.

Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis

2021 ◽  
Author(s):  
Jingjing Wang ◽  
Huixin Peng ◽  
Ayse Anil Timur ◽  
Vinay Pasupuleti ◽  
Yufeng Yao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Endothelial Cell ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Capillary Tube ◽  
Therapeutic Angiogenesis ◽  
Angiogenic Factor ◽  
Single Amino Acid ◽  
Binding Motif ◽  
Cell Functions

Objective: Angiogenic factor AGGF1 (angiogenic factor and G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified α5β1 as the receptor for AGGF1 on ECs. AGGF1 interacts with α5β1 and activates FAK (focal adhesion kinase), Src, and AKT. Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from −RDD- to −RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. Conclusions: We have identified integrin α5β1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of α5β1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with α5β1 and signaling.

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