scholarly journals Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes

2016 ◽  
Vol 113 (8) ◽  
pp. 2104-2109 ◽  
Author(s):  
Ben Murray ◽  
Svetlana V. Antonyuk ◽  
Alberto Marina ◽  
Shelly C. Lu ◽  
Jose M. Mato ◽  
...  
Keyword(s):  
Amino Acid ◽  
Crystal Structures ◽  
Active Site ◽  
Catalytic Site ◽  
Methionine Adenosyltransferase ◽  
Atomic Resolution ◽  
Structural Elements ◽  
Methyl Donor ◽  
Colon Cancers ◽  
Amino Acid Methionine

The principal methyl donor of the cell, S-adenosylmethionine (SAMe), is produced by the highly conserved family of methionine adenosyltranferases (MATs) via an ATP-driven process. These enzymes play an important role in the preservation of life, and their dysregulation has been tightly linked to liver and colon cancers. We present crystal structures of human MATα2 containing various bound ligands, providing a “structural movie” of the catalytic steps. High- to atomic-resolution structures reveal the structural elements of the enzyme involved in utilization of the substrates methionine and adenosine and in formation of the product SAMe. MAT enzymes are also able to produce S-adenosylethionine (SAE) from substrate ethionine. Ethionine, an S-ethyl analog of the amino acid methionine, is known to induce steatosis and pancreatitis. We show that SAE occupies the active site in a manner similar to SAMe, confirming that ethionine also uses the same catalytic site to form the product SAE.

scholarly journals From head to toe of the norovirus 3C-like protease

2012 ◽  
Vol 3 (1) ◽  
pp. 41-56
Author(s):  
Yuichi Someya
Keyword(s):  
Amino Acid ◽  
Active Site ◽  
Viral Protein ◽  
Atomic Resolution ◽  
Viral Gastroenteritis ◽  
Amino Acid Residues ◽  
Viral Protease ◽  
Therapeutic Drugs ◽  
Causative Agents ◽  
Protein Components

AbstractNoroviruses are major causative agents of viral gastroenteritis in humans. Currently, there are no therapeutic medications to treat noroviral infections, nor are there effective vaccines against these pathogens. The viral 3C-like protease is solely responsible for the maturation of viral protein components. The crystal structures of the proteases were resolved at high atomic resolution. The protease was also explored by means of mutagenesis. These studies revealed the active-site amino acid residues and factors determining and affecting substrate specificity as well as the principle of architecting the protease molecule. The possible mechanism of proteolysis was also suggested. Consideration of the data accumulated thus far will be useful for development of therapeutic drugs targeting the viral protease.

Active-Site Architecture of Endopolygalacturonase I fromStereum purpureumRevealed by Crystal Structures in Native and Ligand-Bound Forms at Atomic Resolution†,‡

Biochemistry ◽  
2002 ◽  
Vol 41 (21) ◽  
pp. 6651-6659 ◽  
Author(s):  
Tetsuya Shimizu ◽  
Toru Nakatsu ◽  
Kazuo Miyairi ◽  
Toshikatsu Okuno ◽  
Hiroaki Kato
Keyword(s):  
Crystal Structures ◽  
Active Site ◽  
Atomic Resolution

scholarly journals Crystal structures of sortase B fromStaphylococcus aureusandBacillus anthracisreveal catalytic amino acid triad in the active site

2005 ◽  
Vol 61 (a1) ◽  
pp. c257-c257
Author(s):  
R. Zhang ◽  
R. Wu ◽  
G. Joachimiak ◽  
S. K. Mazmanian ◽  
D. M. Missiakas ◽  
...  
Keyword(s):  
Amino Acid ◽  
Crystal Structures ◽  
Active Site ◽  
Catalytic Amino Acid

scholarly journals Pharmacokinetic properties of a novel formulation of S-adenosyl-l-methionine phytate

Amino Acids ◽  
2021 ◽  
Author(s):  
Antonio Francioso ◽  
Sergio Fanelli ◽  
Maria d’Erme ◽  
Eugenio Lendaro ◽  
Niccolò Miraglia ◽  
...  
Keyword(s):  
Amino Acid ◽  
Steric Hindrance ◽  
Cellular Metabolism ◽  
Food Supplement ◽  
Pharmacokinetic Parameters ◽  
Pharmacological Properties ◽  
Methyl Donor ◽  
Pharmacokinetic Properties ◽  
Amino Acid Methionine ◽  
New Form

AbstractS-adenosyl-l-methionine (SAM), the main endogenous methyl donor, is the adenosyl derivative of the amino acid methionine, which displays many important roles in cellular metabolism. It is widely used as a food supplement and in some countries is also marketed as a drug. Its interesting nutraceutical and pharmacological properties prompted us to evaluate the pharmacokinetics of a new form of SAM, the phytate salt. The product was administered orally to rats and pharmacokinetic parameters were evaluated by comparing the results with that obtained by administering the SAM tosylated form (SAM PTS). It was found that phytate anion protects SAM from degradation, probably because of steric hindrance exerted by the counterion, and that the SAM phytate displayed significant better pharmacokinetic parameters compared to SAM PTS. These results open to the perspective of the use of new salts of SAM endowed with better pharmacokinetic properties.

scholarly journals Characterization, Kinetics, and Crystal Structures of Fructose-1,6-bisphosphate Aldolase from the Human Parasite, Giardia lamblia

2006 ◽  
Vol 282 (7) ◽  
pp. 4859-4867 ◽  
Author(s):  
Andrey Galkin ◽  
Liudmila Kulakova ◽  
Eugene Melamud ◽  
Ling Li ◽  
Chun Wu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Crystal Structures ◽  
Active Site ◽  
Giardia Lamblia ◽  
Conformational Transition ◽  
Crystal Form ◽  
Class Ii ◽  
Zinc Ion ◽  
Class I ◽  
Fructose 1,6 Bisphosphate

Class I and class II fructose-1,6-bisphosphate aldolases (FBPA), glycolytic pathway enzymes, exhibit no amino acid sequence homology and utilize two different catalytic mechanisms. The mammalian class I FBPA employs a Schiff base mechanism, whereas the human parasitic protozoan Giardia lamblia class II FBPA is a zinc-dependent enzyme. In this study, we have explored the potential exploitation of the Giardia FBPA as a drug target. First, synthesis of FBPA was demonstrated in Giardia trophozoites by using an antibody-based fluorescence assay. Second, inhibition of FBPA gene transcription in Giardia trophozoites suggested that the enzyme is necessary for the survival of the organism under optimal laboratory growth conditions. Third, two crystal structures of FBPA in complex with the transition state analog phosphoglycolohydroxamate (PGH) show that the enzyme is homodimeric and that its active site contains a zinc ion. In one crystal form, each subunit contains PGH, which is coordinated to the zinc ion through the hydroxamic acid hydroxyl and carbonyl oxygen atoms. The second crystal form contains PGH only in one subunit and the active site of the second subunit is unoccupied. Inspection of the two states of the enzyme revealed that it undergoes a conformational transition upon ligand binding. The enzyme cleaves d-fructose-1,6-bisphosphate but not d-tagatose-1,6-bisphosphate, which is a tight binding competitive inhibitor. The essential role of the active site residue Asp-83 in catalysis was demonstrated by amino acid replacement. Determinants of catalysis and substrate recognition, derived from comparison of the G. lamblia FBPA structure with Escherichia coli FBPA and with a closely related enzyme, E. coli tagatose-1,6-bisphosphate aldolase (TBPA), are described.

Dual-Function, Light Switchable Cobalt Catalysis via Active Site Metamorphosis

2019 ◽  
Author(s):  
Enrico Bergamaschi ◽  
Frédéric Beltran ◽  
Christopher Teskey
Keyword(s):  
Visible Light ◽  
Active Site ◽  
Catalytic Site ◽  
Dual Function ◽  
Catalytic Systems ◽  
Hydride Complex ◽  
Dual Functional ◽  
Multiple Processes ◽  
Olefin Migration

<p></p><p></p><p>Switchable catalysis offers opportunities to control the rate or selectivity of a reaction <i>via</i> a stimulus such as pH or light. However, few examples of switchable catalytic systems that can facilitate multiple processes exist. Here we report a rare example of such dual-functional, switchable catalysis. Featuring an easily prepared, bench-stable cobalt(I) hydride complex in conjunction with pinacolborane, we can completely alter the reaction outcome between two widely employed transformations – olefin migration and hydroboration – with visible light as the sole trigger. This dichotomy arises from ligand photodissociation which leads to metamorphosis of the active catalytic site, resulting in divergent mechanistic pathways.</p><p></p><p></p>

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