Scientists reveal distinct substrate-binding mode in o-succinylbenzoyl-CoA synthetaseSeptember 13, 2017
o-Succinylbenzoyl-CoA (OSB-CoA) synthetase (MenE) is an essential enzyme in bacterial vitamin K biosynthesis and an important target in the development of new antibiotics. It is a member of the adenylating enzymes (ANL) family, which reconfigure their active site in two different active conformations, one for the adenylation half-reaction and the other for a thioesterification half-reaction, in a domain-alternation catalytic mechanism. Although several aspects of the adenylating mechanism in MenE have recently been uncovered, its thioesterification conformation remains elusive.
Using a catalytically competent Bacillus subtilis mutant protein complexed with an OSB-CoA analogue, researchers from the Hong Kong University of Science and Technology revealed a thioesterification active site specifically conserved among MenE orthologues and a substrate-binding mode distinct from those of many other acyl/aryl-CoA synthetases. Several residues that specifically contribute to the thioesterification half-reaction without affecting the adenylation half-reaction were identified, and they also observed a substantial movement of the activated succinyl group in the thioesterification half-reaction.
Their findings were published in the Journal of Biological Chemistry on July 21, 2017 (doi: 10.1074/jbc.M117.790410).
"Our findings provide new insights into the domain-alternation catalysis of a bacterial enzyme essential for vitamin K biosynthesis, and of its adenylating homologues in the ANL enzyme family," said Zhihong Guo, an associate professor at the Department of Chemistry of HKUST. "Our work validated the hypothesis that a distinct substrate binding mode is unique to this enzyme."
As a member of the ANL enzyme family, OSB-CoA synthetase (MenE) is a valuable drug target in the vitamin K biosynthetic pathway, but little is known about the structure of the enzyme yet.
"We have constructed high-resolution crystal structures of a catalytically competent double mutant (IRAK) of bsMenE in complex with a stable product analogue, OSB-NCoA, and a combination of OSB-NCoA and AMP," said Guo. "In addition, these crystal structures revealed the amino acid residues contributing to recognition and binding of the substrates and products in the thioesterification reaction. These results have not only provided unambiguous support for the domain-alternation catalytic mechanism of ANL enzymes in general; they have also revealed the unique thioesterification active site of OSB-CoA synthetases and provided the structural basis for their catalysis of the thioesterification reaction to facilitate their utility as a drug target."
"Our findings provide fresh insights into the domain-alternation mechanism of the essential vitamin K biosynthetic enzyme and its homologues in the ANL enzyme family, and will help us build a protein catalytic cycle in a continuous manner, which no one has done before."
Hong Kong University of Science and Technology
Related Enzyme Articles:
Oxazaphosphorine cytostatics (Cyclophosphamide, Ifosfamide) are often used and very effective anticancer agents; but so far little is known about the molecular basis for the antitumor effect.
Enzyme follows a two-step verification system before cutting and repairing DNA damage.
An enzyme that blocks cellular senescence and its mechanisms has been discovered by a Japanese research team.
University of California, Riverside-led research finds enzyme that is key to learning in fruit flies.
A team of researchers at the University of Delaware has discovered a new function for an enzyme that has long been known to have a central role in bacterial metabolism.
Depression is the predominant mental disease and constitutes the most common cause of morbidity in developed countries.
International team led by University of Leicester unveil a hidden step in enzyme mechanism.
Scientists at Washington University in St. Louis have isolated the first enzyme shown to be capable of controlling the levels of two distinct plant hormones, involved both in normal growth and in responses to infections.
Scientists at MIT and the University of São Paulo in Brazil have identified the structure of an enzyme that could be a good target for drugs combatting three diseases common in the developing world.
The congenital disease favism causes sickness and even jaundice in patients after they consume beans.
Related Enzyme Reading:
Enzymes: What the Experts Know
by Tom Bohager (Author)
This book throughly describes the role of Enzymes Therapy in restoring, promoting and maintaing optimal health. The topics covered in depth are as follows; Definition of what an Enzyme is, the 4 types, the history of enzyme therapy, animal vs plant-based enzyme therapy, the digestive system, the use of therapeutic enzymes, specific enzymes in therapy, determining enzyme potency, proper pH, the microlflora (bacteria) connection, the immune system, physical fitness, choosing the correct supplement, enzyme deficiency testing, proteases and their effect on probiotics and a discussion of... View Details
Enzymes: The Key to Health, Vol. 1 (The Fundamentals)
by Howard F., Jr. Loomis (Author)
Book by Loomis, Howard F., Jr. View Details
The Enzyme Factor
by Hiromi Shinya MD (Author)
In The Enzyme Factor, Dr. Hiromi Shinya presents his research, grounded in his 45 years of medical practice in the United States and Japan. This research supports the idea of a miracle enzyme out of which all the enzymes the body needs are produced. He suggests cancer and other diseases occur when this key enzyme is depleted and cannot properly do its job. In this book he clearly shows how what we eat affects that key. Dr. Shinya's science is clearly explained and easy to understand. The suggestions for diet and lifestyle based on this science are simple and easy to follow. Even those... View Details
Enzymes: The Missing Link to Health
by Susan M. Lark M.D. (Author)
Do you want relief from colds and flus, allergies, autoimmune disease, heart disease and many other major health issues? Would you like to enjoy a high level of energy and vitality and great resistance to disease? Then Enzymes: The Missing Link to Health is a must read book for you.
Written by Susan M. Lark, M.D., one of the most renowned women’s alternative medicine experts, this comprehensive guide will help to support and restore your own enzyme production for excellent health.
Abundant enzyme production plays a crucial role in protecting and helping us recover from... View Details
by Dr. Edward Howell (Author)
Why is eating food in its natural state, unprocessed and unrefined, so vital to the maintenance of good health? What is lacking in our modern diet that makes us so susceptible to degenerative disease? What natural elements in food may play a key role in unlocking the secrets of life extension? These fascinating questions, and many more, are answered in Enzyme Nutrition.
Written by one of America’s pioneering biochemists and nutrition researchers, Dr. Edward Howell, Enzyme Nutrition presents the most vital nutritional discovery since that of vitamins and... View Details
The Enzyme Advantage: For Health Care Providers And People Who Care About Their Health
by Dr. Howard F Loomis Jr. (Author), Arnold Mann (Author)
Why should you care about food enzymes? This newly-released book includes the answer to that question- as well as how to identify protein, carbohydrate and fat deficiency in yourself and/or your patients. The “Father of Enzyme Nutrition,” Dr. Howard F. Loomis, Jr., has co-authored this book with respected medical journalist Arnold Mann. “Dr. Loomis’ knowledge of enzymes and their diverse functions is truly amazing. It is from the recognition and application of these insights that Dr. Loomis has achieved such an effective tool for acquiring individual wellness.” ~Gary Hayes, M.D. ... View Details
Enzymes: Go With Your Gut: More Practical Guidelines For Digestive Enzymes
by Karen DeFelice (Author)
Karen DeFelice follows up her two previous books on the subject of enzymes with her latest release, a look at enzyme therapy which updates the reader on the latest developments in the field and makes the information practical for everyday use. View Details
Enzymes: An Easy To Understand Guide On Digestive Enzymes And The Vital Functions They Perform In Your Body
by Clara Barnes (Author)
Are you interested in learning more about your body? Do you want to be as health conscious as you can? There are many substances and compounds that allow the human body to function properly. One of the vital substances is the enzymes which sustain life through their metabolic process. Enzymes are large biological molecules that are protein in nature. Enzymes work as catalysts in the body accelerating the metabolic reactions like the digestion. Since the enzymes are protein in nature, they contain several amino acids that are joined together. The enzymes in the body work on a specific... View Details
Enzymes: The Sparks of Life (Natural Health Guide)
by Anthony J. Cichoke (Author)
This Natural Health Guide is chock full of practical information on enzymes, and gives you easy tips to take charge of your life and improve your daily food habits. Discover how increased enzyme intake can slow aging, increase vitality, improve digestion, increase circulation, and reduce inflammation. Includes recipes for enzyme-rich foods to soothe your palate and give you better health. Full-color photos illustrate how appetizing the dishes are. View Details
Enzymes: The Fountain of Life
by K. Miehlke (Author), R. M. Williams (Author), D. A. Lopez (Author)
Enzymes are the essential biochemical units of all forms of life. These natural catalysts represent the labor force of all living organisms. they are involved in all our functions, from birth through advanced age. View Details