Coenzyme biosynthesis: enzyme mechanism, structure and inhibition

2007 ◽  
Vol 24 (5) ◽  
pp. 1009 ◽  
Author(s):  
Duncan E. Scott ◽  
Alessio Ciulli ◽  
Chris Abell
Keyword(s):  
Enzyme Mechanism ◽  
Coenzyme Biosynthesis

ChemInform Abstract: Coenzyme Biosynthesis: Enzyme Mechanism, Structure and Inhibition

ChemInform ◽  
2008 ◽  
Vol 39 (1) ◽  
Author(s):  
Duncan E. Scott ◽  
Alessio Ciulli ◽  
Chris Abell
Keyword(s):  
Enzyme Mechanism ◽  
Coenzyme Biosynthesis

Protein Flexibility Catalyzes a Cell Signaling Reaction of the Ras-GAP Complex

2019 ◽  
Author(s):  
Keiei Kumon ◽  
Masahiro Higashi ◽  
Shinji Saito ◽  
Shigehiko Hayashi
Keyword(s):  
Cell Signaling ◽  
Conformational Changes ◽  
Catalytic Reaction ◽  
Protein Complex ◽  
Enzyme Mechanism ◽  
Activation Free Energy ◽  
Chemical Catalysis ◽  
Simple Chemical ◽  
A Cell ◽  
Enzyme Molecules

Many enzyme molecules exhibit characteristic global and slow dynamics which furnish them with allostery realizing remarkable molecular functionalities more than simple chemical catalysis. However, molecular mechanism of a catalytic reaction associated with the molecular flexibility of enzymes is not well-understood. Here we report a hybrid molecular simulation study on GTPase activity of a Ras-GAP protein complex for cell signaling termination. We unveiled that extensive conformational changes of the protein complex and exclusion of internal water molecules are induced upon the transition state (TS) formation in the catalytic reaction and significantly lower the reaction activation free energy. We also revealed that tumor-related mutations perturb those conformational changes upon the TS formation, leading to reduction of the catalytic activity. The findings of the remarkably dynamic protein conformation directly linking to the catalytic reaction have broad implications for understanding of enzyme mechanism and for developments of allosteric drugs and novel catalysts.

Molecular function of the prolyl cis/trans isomerase and metallochaperone SlyD

2013 ◽  
Vol 394 (8) ◽  
pp. 965-975 ◽  
Author(s):  
Michael Kovermann ◽  
Franz X. Schmid ◽  
Jochen Balbach
Keyword(s):  
Molecular Chaperone ◽  
Molecular Basis ◽  
Catalytic Efficiency ◽  
Enzyme Mechanism ◽  
Molecular Function ◽  
Twin Arginine Translocation ◽  
Chaperone Function ◽  
Nickel Binding ◽  
Biophysical Analysis ◽  
Optimal Function

Abstract SlyD is a bacterial two-domain protein that functions as a molecular chaperone, a prolyl cis/trans isomerase, and a nickel-binding protein. This review summarizes recent findings about the molecular enzyme mechanism of SlyD. The chaperone function located in one domain of SlyD is involved in twin-arginine translocation and increases the catalytic efficiency of the prolyl cis/trans isomerase domain in protein folding by two orders of magnitude. The C-terminal tail of SlyD binds Ni2+ ions and supplies them for the maturation of [NiFe] hydrogenases. A combined biochemical and biophysical analysis revealed the molecular basis of the delicate interplay of the different domains of SlyD for optimal function.

A High-Throughput Liposome Substrate Assay with Automated Lipid Extraction Process for PI 3-Kinase

2008 ◽  
Vol 13 (9) ◽  
pp. 906-911 ◽  
Author(s):  
Trupti Lingaraj ◽  
John Donovan ◽  
Zhi Li ◽  
Ping Li ◽  
Amanda Doucette ◽  
...  
Keyword(s):  
High Throughput ◽  
Lipid Extraction ◽  
Extraction Process ◽  
Enzyme Mechanism ◽  
Class I ◽  
Lipid Kinase ◽  
Chromatography Analysis ◽  
Regulate Cell Growth ◽  
Lipid Kinases ◽  
Layer Chromatography

The signaling pathways involving lipid kinase class I phosphatidylinositol 3-kinases (PI 3-kinases) regulate cell growth, proliferation, and survival. Class I PI 3-kinases catalyze the conversion of PI (4,5)P2 to PI (3,4,5)P3, which acts as a lipid second messenger to activate mitogenic signaling cascades. Recently, p110α, a class IA PI 3-kinase, was found to be mutated frequently in many human cancers. Therefore, it is increasingly studied as an anticancer drug target. Traditionally, PI 3-kinase activities have been studied using liposome substrates. This method, however, is hampered significantly by the labor-intensive manual lipid extraction followed by a low-throughput thin-layer chromatography analysis. The authors describe a high-throughput liposome substrate-based assay based on an automated lipid extraction method that allows them to study PI 3-kinase enzyme mechanism and quantitatively measure inhibitor activity using liposome substrates in a high-throughput mode. This improved assay format can easily be extended to study other classes of phosphoinositide lipid kinases. ( Journal of Biomolecular Screening 2008:906-911)

Chemistry's prodigal child: enzyme mechanism

2008 ◽  
Vol 12 (5) ◽  
pp. 529-531
Author(s):  
Gideon J Davies ◽  
James H Naismith
Keyword(s):  
Enzyme Mechanism

scholarly journals NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Angel L. Pey ◽  
Clare F. Megarity ◽  
David J. Timson
Keyword(s):  
Active Sites ◽  
Physiological Role ◽  
Polymorphic Form ◽  
Normal Function ◽  
Enzyme Mechanism ◽  
Quinone Oxidoreductase ◽  
Lower Stability ◽  
Increased Risk ◽  
Wide Range ◽  
The Right

AbstractNAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease.

scholarly journals Pyruvate kinases have an intrinsic and conserved decarboxylase activity

2014 ◽  
Vol 458 (2) ◽  
pp. 301-311 ◽  
Author(s):  
Wenhe Zhong ◽  
Hugh P. Morgan ◽  
Matthew W. Nowicki ◽  
Iain W. McNae ◽  
Meng Yuan ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Dicarboxylic Acids ◽  
Enzyme Mechanism ◽  
Decarboxylase Activity ◽  
Solution Studies ◽  
Pyruvate Kinases

We provide an enzyme mechanism for the decarboxylase activity of pyruvate kinase which is conserved from protozoa to mammals. Structural and solution studies of range of related dicarboxylic acids suggest the decarboxylase activity is restricted to oxaloacetate as a substrate.

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