Scientists interpret "dead enzyme": existence is reasonable

  Pseudoenzymes can prompt us to think about a problem that we don't really know about kinases   Photo source: Hal mayforth   Reporter Tang Feng   About 10 years ago, biologists began to realize that some human enzymes, like "Squibs", had no catalytic function, which surprised them This kind of cognition is an impact, and human survival is inseparable from enzyme, because enzyme can promote the biochemical reaction on which biological system depends So why do these enzymes lose their catalytic function? Why does the human body continue to retain the ability to produce these inert proteins?   In 2002, this enzyme, called pseudoenzyme, was discovered on a large scale At the time, a research team was combing the latest available human genome sequence diagrams to identify all the genes involved in coding protein kinases These important enzymes act as "switches" in the intracellular molecular circuits, transferring phosphate groups to various targets to help control a wide range of activities, such as metabolism and cell movement   The researchers found that about 10% of 518 DNA encoded human protein kinases lack at least one of the three key amino acids that catalyze phosphate conversion, so they seem to be ineffective Although these invalid enzymes have been known before, the number of false enzymes is so surprising Gerard Manning, the research leader and director of bioinformatics and computational biology of California gene technology company, said: "we thought we were wrong at that time."   But further research confirms that they are right Almost every enzyme family contains inactive members In groups such as sulfatase, more than half of the proteins encoded by human genes show signs of catalytic compromise And the "dead" enzymes that appear in organisms are as diverse as bacteria, plants and mites   False enzyme is not false   Manning and others have determined that these pseudoenzyme genes are not degraded DNA Cells make these proteins, but over millions of years of evolution, their DNA sequences have changed little Some people firmly believe that these proteins have their own functions "Biological systems don't keep these proteins until they have an important role to play." Said Patrick Eyers, a biochemist at the University of Sheffield in the UK   It is true Scientists now speculate that inactivated enzymes may be "hired at a high salary" by organisms, which are not catalysts but play other roles Some of them help catalyse biochemical reactions by forcing "real enzymes" into the right shape, others provide a platform for protein mixing, and some combine with receptors to help cells communicate, protect proteins to new positions like bodyguards, or accomplish other tasks "They have proved to be biologically important." "That's probably why they've been preserved," said Susan Taylor, a protein chemist at the University of California, San Diego   Daan van Aalten, a biochemist at the University of Dundee in the UK, called the pseudoenzymes encoded by DNA sequences "forgotten memories" because most researchers ignored them But molecular biologists now expect the enzyme to help understand the evolution of the enzyme Drug developers hope to develop them for safer, more specific drugs And pseudoenzymes also prompted biochemists to reflect on some of their ideas about how traditional enzymes work "If I start a new research direction again, I will choose pseudoenzyme." Dario Alessi, a biochemist also from Dundee University, said   Root tracing   To study pseudoenzymes, researchers first need to understand them, but it's not easy A candidate amino acid sequence showed that pseudoenzyme had catalytic compromise, but it was not sure So researchers often judge the 3D structure of a protein, test whether it can perform the expected biochemical reaction of an enzyme, and other experiments Even so, the evidence is not always awesome   Despite the uncertainty, it has been thought that the main function of some proteins that look like enzymes does not include catalyzing various reactions Most pseudoenzymes are closely related to active enzymes, and researchers have proposed two evolutionary explanations for this association Both views point to the occurrence of gene replication at some time in the past   The researchers think the more common explanation is that the original and duplicated genes of a normal enzyme mutate, destroying the activity of the enzyme, thus producing a pseudoenzyme "The loss of enzyme function is very simple because the residue of catalytic reaction (amino acid) is easy to preserve." Janet Thornton, a computational biologist and director of the European Institute of bioinformatics in the UK, said   In some cases, the process goes in the opposite direction, Alessi points out: "my theory is that an active kinase may have evolved from a pseudoenzyme." Under this assumption, when gene replication occurs, pseudoenzymes already exist and deal with some non catalytic aspects of cell work After that, the pseudoenzyme mutated and produced the active normal enzyme Some inactivated enzymes do resemble the ancestors of true enzymes: their functional offspring are recognizable because other members of the immediate family are not enzymes   False truth   The cells are full of many excellent proteins Why do these defective enzymes perform important tasks? Perhaps the pseudoenzymes evolved from functional enzymes lost their catalytic function, but they retained other capabilities For example, before an enzyme catalyzes a chemical reaction, it will seize the target molecule or enzyme reactant Their inactive offspring usually maintain this binding property, which means they can target and track proteins for other purposes   Matthew Freeman, a cell biologist at Oxford University, notes that inactivated enzymes share other similarities with their active relatives They often "hang out" in the same organization at the same time So a pseudoenzyme "acts perfectly as a manager" and helps control biochemical reactions, said Margaret Phillips, a biochemist at the Southwestern Medical Center at the University of Texas at Dallas "In many cases, pseudoenzymes can regulate reactions involving their active relatives." Freeman said   Strap α can show how the binding ability of one pseudoenzyme enables it to control other enzymes It can adhere to and regulate the activity of LKB1, a tumor suppressor kinase, which is not active in some cancer cells In a 2009 paper published in science, Alessi, van Aalten and colleagues discussed how strap alpha works With the help of another protein MO25 α, strap α can lock LKB1 in an active state and allow it to work Van Aalten said the study suggested that pseudoenzymes are likely to activate kinases by binding   Towards practicality   Some scientists suggest that pseudoenzyme may be a drug target due to its ability to control enzyme activity, although no such drug is currently in use Eyers pointed out that the study of inactivated kinase may provide an alternative to traditional kinase inhibitors Kinase inhibitors are a rapidly growing class of drugs with nearly $11 billion in sales in the United States alone One of the most famous kinase inhibitors may be Gleevec, which entered the clinical practice in 2001 to treat chronic myeloid leukemia   However, this kind of kinase inhibitor also has defects, because the active site of kinase is very similar to other enzymes, and drugs that can prevent one kinase can also interfere with other enzymes, triggering side effects In the case of Gleevec, this kinase inhibitor can cause abdominal pain, nausea, fatigue and other problems, mainly because these inhibitors are difficult to achieve specificity However, indirect blocking of an overactive and pathogenic kinase by targeting its pseudoenzyme partners may not damage other kinases   However, there are still questions about the value of pseudoenzymes, said Mark Lemmon, a biochemist at the University of Pennsylvania Researchers have rich experience in designing drugs to block kinases, but it is a challenge to design a drug that can block pseudokinases, because traditional and well-studied enzyme active sites are not the natural sites of attack "They may still be important drug targets, and we just need to think about how to inhibit them from different perspectives." He said   Although pseudoenzyme has not yet had an important practical effect, it does play a theoretical role "Pseudoenzymes can prompt us to think about a problem that we don't really know about kinases," says Eyers As a result, biochemists decided to focus on fundamental issues for a second time, such as how active an enzyme is to be considered functional   On a broader scale, the discovery of this new enzyme reveals that only a tiny number of researchers understand some parts of the gene "I'm fascinated by the idea that we don't know a lot about genes," Freeman said   China Science Daily (2013-04-11 3rd Edition International)