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3.3: Enzyme Regulation - Biology

3.3: Enzyme Regulation - Biology


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null Learning Objectives

  1. Compare and contrast the genetic control of enzyme activity (enzyme synthesis) in bacteria with the control of enzyme activity through feedback inhibition.
  2. Compare and contrast an inducible operon with a repressible operon and give an example of each.
  3. Compare how the presense or absence of tryptophan affects the trp operon.
  4. Compare how the presense or absence of lactose affects the lac operon.
  5. Compare how the presense or absence of an inducer affects activators.
  6. Briefly describe how small RNAs can regulate enzyme activity.
  7. Define the following:
    1. repressor
    2. inducer
    3. activator
    4. enhancer
    5. small RNAs
  8. Compare and contrast competitive inhibition with noncompetitive inhibition.

In living cells, there are hundreds of different enzymes working together in a coordinated manner. Living cells neither synthesize nor break down more material than is required for normal metabolism and growth. All of this necessitates precise control mechanisms for turning metabolic reactions on and off. There is tremendous diversity in the mechanisms bacteria use to regulate enzyme synthesis and enzyme activity. For pretty much every step between the activation of a gene and the final enzyme reaction from that gene product there is some bacterial mechanism for regulation that step. Here we will look at several well studied examples.

Genetic Control of Enzyme Synthesis through Repression, Induction, or Enhancement of Transcription

Genetic control of enzyme activity refers to controlling transcription of the mRNA needed for an enzyme's synthesis. In prokaryotic cells, this involves the induction, repression, or enhancement of enzyme synthesis by regulatory proteins that can bind to DNA and either induce, block, or enhance the function of RNA polymerase , the enzyme required for transcription. The regulatory proteins are often part of either an operon or a regulon. An operon is a set of genes transcribed as a polycistronic message that is collectively controlled by a regulatory protein. A regulon is a set of related genes controlled by the same regulatory protein but transcribed as monocistronic units. Regulatory proteins may function either as repressors, activators, or enhancers.

A. Repressors

Repressors are regulatory proteins that block transcription of mRNA. They do this by binding to a portion of DNA called the operator (operators are often called boxes now) that lies downstream of a promoter. The binding of the regulatory protein to the operator prevents RNA polymerase from binding to the promoter and transcribing the coding sequence for the enzymes. This is called negative control and is mostly n in biosynthetic reactions where a bacterium only makes a molecule like a particular amino acid when that amino acid is not present in the cell.

Repressors are allosteric proteins that have a binding site for a specific molecule. Binding of that molecule to the allosteric site of the repressor can alter the repressor's shape that, in turn affects its ability to bind to DNA. This can work in one of two ways:

1. Some repressors are synthesized in a form that cannot by itself bind to the operator. This is referred to as a repressible system. The binding of a molecule called a corepressor, however, alters the shape of the regulatory protein to a form that can bind to the operator and subsequently block transcription. An example of this type of repressible system is the trp operon in Escherichia coli that encodes the five enzymes in the pathway for the biosynthesis of the amino acid tryptophan. In this case, the repressor protein coded for by the trp regulatory gene, normally does not bind to the operator region of the trp operon and the five enzymes needed to synthesize the amino acid tryptophan are made (Figure (PageIndex{1})A and Figure (PageIndex{1})B).

Tryptophan, the end product of these enzyme reactions, however, functions as a corepressor. Once sufficient tryptophan has been synthesized, the cell needs to terminate its synthesis. The tryptophan is able to bind to a site on the allosteric repressor protein, changing its shape and enabling it to interact with the trp operator region. Once the repressor binds to the operator, RNA polymerase is unable to bind to the promoter and transcribe the genes for tryptophan biosynthesis. Therefore, when sufficient tryptophan is present, transcription of the enzymes that allows for its biosynthesis are turned off ( Figure (PageIndex{2})A and Figure (PageIndex{2})B).

In addition to repression, the expression of the trp operon is also regulated by attenuation. The trpL gene codes for a mRNA leader sequence that controls operon expression through attenuation. This leader sequence mRNA consists of domains 1, 2, 3, and 4. Domain 3 can base pair with either domain 2 or domain 4.

At high tryptophan concentrations, domains 3 and 4 pair in such a way as to form stem and loop structures that block the transcription of the remainder of the leader sequence mRNA and subsequently, the transcription of the structural genes for tryptophan biosynthesis ( Figure (PageIndex{3})A). However, at low concentrations of tryptophan, domains 3 and 2 pair. This pairing allows for the full transcription of the leader sequence mRNA, as well as that of the structural genes for tryptophan biosynthesis ( Figure (PageIndex{3})B).

2. Other repressors are synthesized in a form that readily binds to the operator and blocks transcription. However, the binding of a molecule called an inducer alters the shape of the regulatory protein in a way that now blocks its binding to the operator and thus permits transcription. This is referred to as an inducible system.

An example of an inducible system is the lac operon that encodes for the three enzymes needed for the degradation of lactose by E. coli. E. coli will only synthesize the enzymes it requires to utilize lactose if that sugar is present in the surrounding environment. In this case, lactose functions as an inducer . In the absence of lactose, the active repressor protein binds to the operator and RNA polymerase is unable to bind to the promoter and transcribe the genes for utilization of lactose. As a result, the enzymes needed for the utilization of lactose are not synthesized (Figure (PageIndex{4})A and Figure (PageIndex{4})B). When lactose, the inducer, is present, a metabolite of lactose called allolactose binds to the allosteric repressor protein and causes it to change shape in such a way that it is no longer able to bind to the operator. Now RNA polymerase is able to transcribe the three lac operon structural genes and the bacterium is able to synthesize the enzymes required for the utilization of lactose (Figure (PageIndex{5})A and Figure (PageIndex{5})B).

B. Activators

Activators are regulatory proteins that promote transcription of mRNA. Activators control genes that have a promotor to which RNA polymerase cannot bind. The promotor lies adjacent to a segment of DNA called the activator-binding site. The activator is an allosteric protein synthesized in a form that cannot normally bind to the activator-binding site. As a result, RNA polymerase is unable to bind to the promoter and transcribe the genes ( Figure (PageIndex{6})). However, binding of a molecule called an inducer to the activator alters the shape of the activator in a way that now allows it to bind to the activator-binding site. The binding of the activator to the activator-binding site, in turn, enables RNA polymerase to bind to the promotor and initiate transcription ( Figure (PageIndex{7})A and Figure (PageIndex{7})B). This is called positive control and is mostly n in catabolic reactions where a bacterium only makes enzymes for the catabolism of a substrate when that substrate is available to the cell.

C. Enhancers

Enhancers are regulatory proteins that bind to DNA located some distance from the operon they control by working with DNA-bending proteins. The DNA-binding proteins bend the DNA in a way that now allows the enhancer to interact with the promoter in such a way that RNA polymerase can now bind and initiate transcription ( Figure (PageIndex{8})).

2. Genetic Control of Enzyme Synthesis through Promoter Recognition and through DNA Supercoiling

a. Promoter Recognition: The specific sigma factors that bind to RNA polymerase determine which operon will be transcribed.

b. DNA Supercoiling: DNA supercoiling can change the tertiary shape of a DNA molecule from its normal form to one that has a left-handed twist called Z-DNA. The activities of some promoters are decreased with Z-DNA while others are increased.

3. Genetic Control of Enzyme Synthesis through the Translational Control of Enzyme Synthesis

a. RNA interference (RNAi)

RNA interference (RNAi) is a process whereby small non-coding regulatory RNAs (ncRNAs) such as microRNAs (miRNAs) regulate gene expression. These ncRNAs are regulatory molecules that are complementary to an early portion of the 5' end of the mRNA coding for the enzyme. When the small RNA binds to the mRNA by complementary base pairing , ribosomes cannot attach to the mRNA blocking its translation. As a result, the enzyme is not made ( Figure (PageIndex{9})). In bacteria these ncRNAs are often called small RNAs (sRNAs); in animal cells, plant cells, and viruses they are often called microRNAs (miRNA).

b. Ribosomal Proteins (r-proteins)

Ribosomal proteins bind to rRNA to form ribosomal subunits. Because the nucleotide base sequence for the mRNA coding for the r-proteins has similarities to that of the rRNA to which that r-protein binds during subunit formation, r-proteins not yet incorporated into ribosomal subunits can bind to that mRNA and block translation

4. Controlling the Enzyme's Activity (Feedback Inhibition).

Enzyme activity can be controlled by competitive inhibition and non-competitive inhibition.

a. With what is termed non-competitive inhibition , the inhibitor is the end product of a metabolic pathway that is able to bind to a second site (the allosteric site) on the enzyme. Binding of the inhibitor to the allosteric site alters the shape of the enzyme's active site thus preventing binding of the first substrate in the metabolic pathway. In this way, the pathway is turned off ( Figure (PageIndex{10})).

b. In the case of what is called competitive inhibition , the inhibitor is the end product of an enzymatic reaction. That end product is also capable of reacting with the enzyme's active site and prevents the enzyme from binding its normal substrate. As a result, the end product is no longer synthesized ( Figure (PageIndex{11})).

Summary

  1. In living cells there are hundreds of different enzymes working together in a coordinated manner, and since cells neither synthesize nor break down more material than is required for normal metabolism and growth, precise enzyme regulation is required for turning metabolic reactions on and off.
  2. There is tremendous diversity in the mechanisms bacteria use to regulate enzyme synthesis and enzyme activity.
  3. Ways in which enzymes can be controlled or regulated include controlling the synthesis of the enzyme (genetic control) and controlling the activity of the enzyme (feedback inhibition).
  4. In prokaryotes, genetic control of enzyme activity includes the induction or repression of enzyme synthesis by regulatory proteins that can bind to DNA and either block or enhance the function of RNA polymerase, the enzyme required for transcription.
  5. An operon is a set of genes collectively controlled by a regulatory protein.
  6. Regulatory proteins may function either as repressors or activators.
  7. Repressors are regulatory proteins that block transcription of mRNA by preventing RNA polymerase from transcribing the coding sequence for the enzymes.
  8. Some repressors, as in the case of the trp operon, are synthesized in a form that cannot by itself bind to the operator. The binding of a molecule called a corepressor, however, alters the shape of the regulatory protein to a form that can bind to the operator and subsequently block transcription.
  9. Some repressors, as in the case of the lac operon, are synthesized in a form that readily binds to the operator and blocks transcription. This is referred to as an inducible system.
  10. Activators are regulatory proteins that promote transcription of mRNA by enabling RNA polymerase to transcribing the coding sequence for the enzymes.
  11. Enhancers are regulatory proteins that bind to DNA located some distance from the operon they control by working with DNA-bending proteins. The DNA-bending proteins bend the DNA in a way that now allows the enhancer to interact with the promoter in such a way that RNA polymerase can now bind and initiate transcription
  12. Bacteria also use translational control of enzyme synthesis. One method is for the bacteria to produce noncoding RNA (ncRNA) molecules that are complementary to the mRNA coding for the enzyme, and when the small RNA binds to the mRNA by complementary base pairing, ribosomes cannot attach to the mRNA, the mRNA is not transcribed and translated into protein, and the enzyme is not made. In bacteria, these ncRNAs are often called small RNAs (sRNAs).
  13. Feedback inhibition controls the activity of the enzyme rather than its synthesis and can be noncompetitive or competitive.
  14. In the case of non-competitive inhibition, the inhibitor is the end product of a metabolic pathway that is able to bind the allosteric site on the enzyme. In this way, the pathway is turned off.
  15. In the case of what is called competitive inhibition, the inhibitor is the end product of an enzymatic reaction. As a result, the end product is no longer synthesized.

3.3: Enzyme Regulation - Biology

RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme [4] that in humans is encoded by the RAF1 gene. [5] [6] The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases. [7] C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.


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Grade Mode: S/U Sat/Unsat Only.
Special Course Fee: No.

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring, Summer.
Grade Mode: S/U Sat/Unsat Only.
Special Course Fee: No.

BC𧎽  Grant Proposal Writing and Reviewing  Credit: 1 (1-0-0)

Course Description: Didactic and hands-on experience with locating funding sources, writing effective grant proposals, and the review process in the bio-molecular sciences.
Prerequisite: (BC𧊓) and (BC𧋿, may be taken concurrently) and (BC𧌳, may be taken concurrently).
Restriction: Must be a: Graduate, Professional.
Term Offered: Fall.
Grade Mode: Instructor Option.
Special Course Fee: No.

BC𧏇A  Advanced Topics in Structural Biology: Protein Structure and Function  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧋿 and BC𧍣.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏇B  Advanced Topics in Structural Biology: Membrane Proteins  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧋿 and BC𧍣.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏇C  Advanced Topics in Structural Biology: Protein-DNA Interactions  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧋿 and BC𧍣.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏇D  Advanced Topics in Structural Biology: Biomolecular Spectroscopy  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧋿 and BC𧍣.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏇E  Advanced Topics in Structural Biology: Biomolecular NMR  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧋿 and BC𧍣.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏇F  Advanced Topics in Structural Biology: Macromolecular X-ray Crystallography  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧋿 and BC𧍣.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏻A  Advanced Molecular Genetics Topics: Chromatin and Transcription  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧎗, may be taken concurrently.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏻B  Advanced Molecular Genetics Topics: Transcriptional Control - Co-Activators and Corepressors  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧎗, may be taken concurrently.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧏻C  Advanced Molecular Genetics Topics: Concepts and Techniques of Genetic Analysis  Credit: 1 (1-0-0)

Course Description:
Prerequisite: BC𧎗, may be taken concurrently.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Traditional.
Special Course Fee: No.

BC𧐐  Supervised College Teaching  Credits: Var[1-3] (0-0-0)

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring, Summer.
Grade Mode: Instructor Option.
Special Course Fee: No.

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring.
Grade Mode: Instructor Option.
Special Course Fee: No.

BC𧐛  Independent Study  Credits: Var[1-18] (0-0-0)

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring, Summer.
Grade Mode: S/U Sat/Unsat Only.
Special Course Fee: No.

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring, Summer.
Grade Mode: S/U Sat/Unsat Only.
Special Course Fee: No.

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring, Summer.
Grade Mode: S/U Sat/Unsat Only.
Special Course Fee: No.

Course Description:
Prerequisite: None.
Restriction: Must be a: Graduate, Professional.
Terms Offered: Fall, Spring, Summer.
Grade Mode: S/U Sat/Unsat Only.
Special Course Fee: No.


EU framework

Previously, food enzymes other than those used as food additives were not regulated at EU level or were regulated as processing aids under the legislation of Member States. Only France and Denmark have required safety evaluations for enzymes used as processing aids before they could be used in food production.

Due to differences between national rules on the assessment and authorisation of food enzymes, new EU framework legislation on food enzymes was adopted in 2008. This legislation has the aim eventually to establish an EU list of enzymes. Until such a list is established national rules on the marketing and use of food enzymes and food produced with food enzymes will continue to apply in EU countries.

Regulation EC 1331/2008 introduced a common approval procedure for additives, enzymes and flavourings used in food. Regulation EC 1332/2008 harmonises rules on enzymes used in foods in the EU and requires the submission of applications for authorisation of all existing and new enzymes prior to their inclusion in an official EU list of approved food enzymes at a future date. This legislation requires EFSA to evaluate the safety of all these food enzymes before they can be authorised in the EU and added to the EU list. A food enzyme will be included in the EU list if it does not pose a health concern to the consumer there is a technological need for its use and its use does not mislead consumers. Labelling requirements for food enzymes are covered by Directive 2000/13/EC and Regulation EC 1332/2008.

The timeframe and the data requirements for submission of applications were established by Regulation EU 234/2011. This regulation establishes a submission period for existing food enzymes starting from 11 September 2011. The deadline for submitting such applications was extended from 24 to 42 months (11 March 2015) by Regulation EU 1056/2012. A further amendment by Regulation EU 562/2012 introduced the possibility of grouping food enzymes under one application to improve the efficiency of the evaluation process, as well as a derogation from submitting toxicological data under certain conditions. These provisions apply only to enzymes with the same catalytic class, manufactured substantially by the same process and originating from the same source, and for enzymes:

  • Already evaluated by France or Denmark (with the exception of those produced by genetically-modified plants, animals or micro-organisms)
  • Produced by microorganisms on EFSA’s Qualified Presumption of Safety list
  • Produced from the edible parts of non-genetically modified plants and animals.

The above-mentioned EU legislation does not cover enzymes intended for human consumption, for example those used for nutritional or digestive purposes, or food enzymes used in the production of food additives (as defined by Regulation EC 1333/2008 on food additives). Also, microbial cultures traditionally used in the production of food (cheese, wine), which may incidentally produce enzymes but are not specifically used to produce them, are not considered food enzymes.

More information on food enzyme legislation and the submission of food enzyme applications:


Enzyme Nomenclature

World Wide Web version prepared by G.P. Moss
School of Biological and Chemical Sciences, Queen Mary University of London,
Mile End Road, London, E1 4NS, UK
[email protected]

To SEARCH for Information on Enzymes on the Database CLICK HERE.

This page contains general information on enzyme nomenclature. It includes links to individual documents, and the number of these will increase as more sections of the enzyme list are revised. Links to other relevant databases are provided. It also provides advice on how to suggest new enzymes for listing, or correction of existing entries. There is a list of abbreviations used in the database.

Historical Introduction

In Enzyme Nomenclature 1992 there was an historical introduction. This web version is slightly edited from that in the book.

Published in Enzyme Nomenclature 1992 [Academic Press, San Diego, California, ISBN 0-12-227164-5 (hardback), 0-12-227165-3 (paperback)] with Supplement 1 (1993), Supplement 2 (1994), Supplement 3 (1995), Supplement 4 (1997) and Supplement 5 (in Eur. J. Biochem. 1994, 223, 1-5 Eur. J. Biochem. 1995, 232, 1-6 Eur. J. Biochem. 1996, 237, 1-5 Eur. J. Biochem. 1997, 250 1-6, and Eur. J. Biochem. 1999, 264, 610-650 respectively) [Copyright IUBMB].

Each enzyme has recorded at the end details of when first published in Enzyme Nomenclature or when added to the database and its subsequent history.

Web Version of Enzyme Nomenclature

The complete contents of Enzyme Nomenclature, 1992 (plus subsequent supplements and other changes) are listed below in enzyme number order giving just the recommended name. Each entry provides a link to details of that enzyme. Alternatively if looking for a specific reaction used in the classification of enzymes the broad outline defined by the first two numbers are given below. Each of these subclass entries is linked to a location where the category is subdivided to sub-subclasses. These in turn are linked to a list of recommended names for each enzyme in the sub-subclass.

The common names of all listed enzymes are listed below, along with their EC numbers. Where an enzyme has been deleted or transferred to another EC number, this information is also indicated. Each list is linked to either separate entries for each entry or to files with up to 50 enzymes in each file.

Glossary, Reaction pathways and Links to Other Databases

A start has been made in showing the pathways in which enzymes participate. Thus, for example, a link under EC 5.3.3.2 (isopentenyl-diphosphate isomerase) leads to the pathway from mevalonate to terpenes, and links under EC 1.14.99.7 (squalene monooxygenase) and EC 5.4.99.7 (lanosterol synthase) lead to pathways of steroid formation. For other enzymes a glossary entry has been added which may be just a systematic name or a link to a graphic representation. The glossary from Enzyme Nomenclature, 1992 may also be consulted. This has been updated with subsequent glossary entries. Each enzyme entry has links to other databases. For recent entries these may not yet have been implemented on the other datebase. For details on the information provided click here.

Enzyme Supplement 6 to 24 (electronic only)

Six documents listing additions and corrections to previous entries were approved in 2000. These together form Supplement 6.

Five documents were approved in 2001 and form Supplement 7.

Three documents (six files) were approved in 2002 and form Supplement 8.

Three documents (five files) were approved in 2003 and form Supplement 9.

Three documents were approved in 2004 and form Supplement 10.

Six documents were approved in 2005 and form Supplement 11.

Four files were approved in 2006 and form Supplement 12.

Two files were approved in 2007 and form Supplement 13.

Eleven files were approved in 2008 and form Supplement 14.

Seven files were approved in 2009 and form Supplement 15.

Seven files were approved in 2010 and form Supplement 16.

Eight files were approved in 2011 and form Supplement 17.

Five files were approved in 2012 and form Supplement 18.

Three files were approved in 2013 and form Supplement 19.

Four files were approved in 2014 and form Supplement 20.

Three files were approved in 2015 and form Supplement 21.

Four files were approved in 2016 and form Supplement 22.

Four files were approved in 2017 and form Supplement 23.

Five files has been approved in 2018 and form Supplement 24.

Four files has been approved in 2019 and form Supplement 25.

The entries are © Copyright to the International Union of Biochemistry and Molecular Biology.

Proposed New Entries and Revised Entries

Proposals for new entries to the Enzyme List and revisions of previously published entries are available from the following file:

Criteria for inclusion

Before an enzyme can be included in the list direct experimental evidence is required that the proposed enzyme actually catalyses the reaction claimed. Close sequence similarity is not sufficient without evidence for the reaction catalysed, because only a small change in sequence is sufficient to change the activity or specificity of an enzyme. Furthermore, because classification is based solely on the reaction catalysed, there are cases where proteins of very different sequences catalyse the same reaction. The existence of an apparent gap in a biochemical pathway, are not, in themselves, sufficient for classification purposes.

How to suggest new entries and correct existing entries

Information about new enzymes or corrections to existing entries may be reported directly from these web pages or by using the form printed in the back of Enzyme Nomenclature. Advice is available on how to suggest new enzymes for listing, or corrections of existing entries. Comments and suggestions on enzyme classification and nomenclature also may be sent to Dr Andrew McDonald (Department of Biochemistry, Trinity College Dublin, Dublin 2, Ireland)

Rules for the Classification and Nomenclature of Enzymes

In Enzyme Nomenclature 1992 there was a section on general principles recommended and systematic names scheme of classification and numbering of enzymes and rules for classification and nomenclature. This web version is slightly edited from that in the book.

The links are to a list of sub-subclasses which in turn list the enzymes linked to separate files for each enzyme, or to a list as part of a file with up to 50 enzymes per file.


From mass fraction to concentration

Throughout, our focus will be on the protein fraction devoted to ribosomal and metabolic proteins, and how the total proteome is partitioned between these two classes to maximize the rate of protein synthesis and cell growth. In terms of the proteome fraction, it is straightforward to invoke constraints linking these two protein classes (Fig 1B). Nevertheless, in large-scale metabolic models, it is more typical to use units of concentration in place of mass fraction. From the proportionality between the total protein mass and the cell's dry mass (Bremer & Dennis, 1996 ), and the constancy in the cell density across nutrient conditions (Kubitschek et al, 1984 ), a quantity normalized by the total protein mass is a proxy for the intracellular concentration, for example, ϕR is proportional to the ribosome concentration. It has been previously estimated that the conversion factor from concentration ci to mass fraction, ϕi = σci, is approximately σ = 3.8 × 10 −7 μM × Naa where Naa is the number of amino acids in the protein of interest (Klumpp et al, 2013 ). For a typical protein of 330 amino acid residues, a mass fraction of 0.1% corresponds to about 8 μM [see also Milo ( 2013 )].


Negative Feedback

Negative feedback is a process that happens when your systems need to slow down or completely stop a process that is happening. When you eat, food travels into your stomach, and digestion begins. You don't need your stomach working if you aren't eating. The digestive system works with a series of hormones and nervous impulses to stop and start the secretion of acids in your stomach. Another example of negative feedback occurs when your body's temperature begins to rise and a negative feedback response works to counteract and stop the rise in temperature. Sweating is a good example of negative feedback.


Molecular Motors

Finally, enzymes can be thought of as nanomachines, powering the reactions of the cell to enable the human body to be the entity it is. There is a special class of enzymes called molecular motors that drive all the movements that occur in the body, including muscle contraction (myosin/actin), flagella and cilia beating (dynein/microtubule), and vesicle movements in neurons (kinesin/microtubule). These molecular motors harness the energy from adenosine triphosphate (ATP) to drive actin-based or microtubulebased movements.


Discussion

Melanin is thought to play an important role in adaptation to changing environments for many fungi. Given its importance, evolution is likely to favor the emergence of genetic mechanisms that enable a variable regulation of melanin accumulation that can balance fitness costs associated with melanin synthesis against the survival advantage that may be gained under hazardous conditions. Here, we demonstrated that differences in regulation of expression of the gene encoding the transcription factor Zmr1 can be governed by both transposable elements and variation in promoter sequences, and contribute to variation in melanization levels.

Alterations in regulatory pathways are known to contribute to natural variation in complex traits and differential regulation of gene expression has long been associated with morphological differences among individuals within plant and animal species. For example, selection by maize breeders for a reduction in branching most probably targeted regulatory differences of the gene encoding the transcription factor Teosinte Branched 1, which represses the growth of axillary meristems [45]. In stickleback fish, the differential expression of a bone morphogenetic protein due to a transposon insertion led to changes in the size of armor plates involved in defense [46]. The diversity of wing pigmentation patterns found in fruit fly species is acquired through regulatory changes affecting enzymes involved in pigment deposition [47, 48]. These examples illustrate well the effects of regulatory pathways on complex traits in model plant and animal species. Although several studies suggested that regulatory changes could also play a role in phenotypic variation in fungi, these studies were limited mainly to yeast [49,50,51,52,53,54]. Much less is known about the importance of regulatory mutations for maintaining phenotypic variation in filamentous fungi [17, 18]. Here we demonstrated a significant effect of variation in cis-regulatory elements on a complex trait in a fungal plant pathogen. Modification of the regulatory sequences of Zmr1 had a major effect on the accumulation of melanin in Z. tritici. Our findings indicate that regulatory modifications can play a major role in fungal adaptation to variable environments. In several recent population genomic analyses of fungi, SNPs significantly associated with a phenotypic trait were identified in non-coding regions of the genome [36, 55]. We hypothesize that these SNPs are involved in modification of regulatory pathways that subsequently lead to the observed phenotypic variation.

Diversity in melanin levels and its role in adaptation

Melanin is a widely distributed compound in eukaryotes that can affect fitness. The biological functions of melanin differ substantially among species [31, 43, 56, 57]. In plant pathogens, such as Pyricularia grisea, Colletotrichum lindemuthianum, and Colletotrichum lagenarium, melanin accumulation in the appressorium is essential for direct penetration of the host epidermis [42, 58]. Because Z. tritici enters the host through the stomata, melanin is not required to initiate infection. The lack of significant differences in virulence between isogenic melanized and non-melanized strains of Z. tritici suggests that melanin does not play a major role in colonization under the tested conditions. However, we cannot discount a virulence function for melanin under natural conditions, where variation in UV radiation, host genotypes, and interactions with other microbes are likely to play important roles. Z. tritici pycnidia are highly melanized, and melanin likely protects the embedded pycnidiospores. In other organisms, melanin shields against stress [43] and the degree of melanization can be correlated with the degree of resistance to stress [59]. We found that melanin can lower sensitivity to an SDHI fungicide (Additional file 13), suggesting that frequent applications of SDHI fungicides onto wheat fields may select for strains that can accumulate higher levels of melanin. The capacity of melanin to shield against toxic compounds could reflect a role for melanin in protection against antimicrobials produced under natural conditions by microbial competitors or by the host [43, 60, 61]. The melanin protection we observed against fungicides was specific. The inability of melanin to protect against azoles might be related to the fact that azoles do not bind to melanin, so azoles can reach their target site even in melanized cells [62]. Though melanin can contribute to survival in fluctuating environments, our experiments indicated that melanin production has a fitness cost that results in reduced growth. We found that Z. tritici strains exhibit temporal differences in melanin accumulation. We postulate that these differences reflect selection operating to balance rates of growth with survival to environmental stress. Under this scenario, melanin accumulation illustrates how a trade-off between adaptation and growth can contribute to variation in a trait.

Variability in melanin accumulation is caused by differential regulation of gene expression

Our approach revealed that variability in melanin accumulation is mediated by differential regulation of expression of the Zmr1 gene. Zmr1 encodes a transcription factor that regulates expression levels of genes in the melanin biosynthetic cluster. We characterized two regulatory layers mediating variation in Zmr1 expression: promoter sequence modifications and an insertion of transposable elements upstream of the promoter. Twelve SNPs in the promoter of Zmr1 underlie differential regulation of melanin accumulation in the light and dark strains. Although the individual effects of these 12 mutations have not yet been tested, we hypothesize that at least one of these promoter mutations alters the levels of Zmr1 transcription.

An island of 13 transposable elements of approximately 30 kb is located upstream of the Zmr1 promoter in the lighter strain and delays Zmr1 expression. We demonstrated the contribution of the transposable elements in downregulating melanin accumulation by removing the entire transposable element island, which led to an increase in Zmr1 expression and melanin accumulation. The transposable element-mediated downregulation of Zmr1 is transient, as the differences in Zmr1 expression between the lighter and darker strain decrease with age. The transposable element island hinders Zmr1 expression either by blocking the activity of activators upstream of the transposable elements or by epigenetically silencing adjacent regions. Remarkably, we observed a silencing effect of the hygromycin resistance gene under the control of a constitutive promoter when it was located at the Zmr1 locus, downstream of the transposable element island in the 3D1 strain. The expression of the hygromycin resistance gene was higher when it was located ectopically or at the Zmr1 locus in the 3D7 background. These findings suggest that the transposable element insertions reduce the expression of Zmr1 in the lighter strain through epigenetic mechanisms.

Transposable elements are frequently associated with heterochromatic regions of the genome and this limits transposable element activity and transcription [40, 63,64,65,66,67]. The spread of the heterochromatic state of the transposable elements to neighboring genes silences their expression, as shown in other organisms [15, 68,69,70,71]. Frequently, under stressful conditions, some families of transposable elements are transcriptionally activated [72,73,74]. This suggests that transposable elements may provide a mechanism to specifically regulate expression of nearby genes under stressful conditions [21, 75, 76]. In Epichloë festucae two genes involved in the synthesis of alkaloids are located in a transposable element-rich region and are epigenetically silenced in axenic culture. Epigenetic silencing and de-silencing were shown to provide an important regulatory layer to specifically produce the alkaloids during host colonization [63]. In the pathogenic fungus Leptosphaeria maculans, effector genes are located in heterochromatic regions rich in transposable elements. Insertions of transposable elements were shown to modify the epigenetic state of nearby effector genes and consequently modulate their expression patterns [77]. In maize, insertion of a transposable element and the resulting spread of DNA and histone methylation marks to the cis-regulatory region of a gene reduces the accessibility for transcription factors and the RNA polymerase, thus altering expression levels upon attack by Fusarium graminearum [15]. We postulate that regulation of Zmr1 by insertions of transposable elements is mediated by similar mechanisms, which involves the spreading of epigenetic marks to Zmr1 in the lighter strain. In this way, transposable element insertions can provide a new layer of gene regulation that can optimize fitness in fluctuating environments.

Genomic rearrangements modulate melanin levels in Z. tritici populations

Two antagonistic consequences of melanin accumulation, protection from stress and decrease in growth rate, suggest the need for variable regulation of melanin synthesis to survive in different environments. During host colonization, Z. tritici is exposed to different micro-climatic conditions and is subjected to environmental changes, depending on its spatial location during host colonization [25, 78]. It is likely that this spatial and temporal environmental heterogeneity leads to diversification of melanization levels in Z. tritici. Fluctuations in macro-climate may also select for diversification in melanization, with episodes of severe heat, cold, drought, or UV radiation likely favoring strains with higher melanization, while less melanized strains may have higher fitness during less stressful weather conditions. The significant variability in the degree of melanization exhibited among different strains of Z. tritici can have many underlying causes, but we hypothesize that most of these differences reflect local adaptation.

The genome of Z. tritici contains approximately 17% repetitive elements [39, 69]. Transposable element insertions can cause adaptive variation and contribute to pathogen evolution. Transposable elements are frequently associated with stress-related genes and are considered to contribute to their diversification [22, 23, 76, 79] but how transposable elements drive adaptation remains to be fully understood. Here we show that transposable elements contribute to phenotypic diversity by regulating gene expression. Independent insertions of transposable elements in Z. tritici contributed to differential regulation of Zmr1 expression and led to diversification of melanin accumulation.


Enzyme Preparations Used in Food (Partial List)

Food ingredients may be "food additives" that are approved by FDA for specific uses or GRAS (generally recognized as safe) substances. A substance may be GRAS only if its general recognition of safety is based on the views of experts qualified to evaluate the safety of the substance. GRAS status may be based either on a history of safe use in food prior to 1958 or on scientific procedures, which require the same quantity and quality of evidence as would be required to obtain a food additive regulation. Because GRAS status may be either affirmed by FDA or determined independently by qualified experts, FDA's regulations do not include all GRAS ingredients and the specific uses described in the GRAS regulations may not be comprehensive for the listed ingredients.

The following list, which derives partially from FDA's regulations in Title 21 of the Code of Federal Regulations (21 CFR), includes approved food additives and substances whose GRAS status has been affirmed by FDA. This list includes some ingredients that are not listed in 21 CFR but have been the subject of opinion letters from FDA to individuals who asked whether FDA would object to the use of the ingredient in food on the basis of an independent GRAS determination. In addition, enzyme preparations may be the subject of a GRAS notice. For further information, consult the GRAS Notice Inventory. Because the list below is not updated on a regular basis, questions about the regulatory status of enzyme preparations that are not on this list may be directed to us via electronic mail at [email protected]

The following is a compilation of enzymes listed as food additives in 21 CFR Part 173. Conditions for their use are prescribed in the referent regulations and are predicated on the use of good manufacturing practices.

Table 1. Enzyme preparations approved as food additives listed in in 21 CFR 173
Section in 21 CFR Description of Enzyme Preparation
§173.110 Amyloglucosidase derived from Rhizopus niveus for use in degrading gelatinized starch into constituent sugars.
§173.120 Carbohydrase and cellulase derived from Aspergillus niger for use in clam and shrimp processing.
§173.130 Carbohydrase derived from Rhizopus oryzae for use in the production of dextrose from starch.
§173.135 Catalase derived from Micrococcus lysodeikticus for use in the manufacture of cheese.
§173.140 Esterase-lipase derived from Mucor miehei var. Cooney et Emerson as a flavor enhancer in cheeses, fats and oils, and milk products.
§173.145 α-galactosidase derived from Mortierella vinaceae var. raffinoseutilizer for use in the production of sucrose from sugar beets.
§173.150 Milk-clotting enzymes, microbial for use in the production of cheese (Milk-clotting enzymes are derived from Endothia parasitica Bacillus cereus, Mucor pusillus Lindt and Mucor miehei Cooney et Emerson and Aspergillus oryzae modified to contain the gene for aspartic proteinase from Rhizomucor miehei var Cooney et Emerson).

The following food standard lists a permitted enzyme preparation

Table 2. Enzyme preparation specified in a food standard
Section in 21 CFR Description of Food
§137.105 Flour may contain α-amylase obtained from the fungus Aspergillus oryzae.

Please be aware that FDA has not affirmed as GRAS all food ingredients that it may consider GRAS. Therefore, the table below does not represent a complete list of all enzymes that FDA may view as GRAS for some uses.

The following is a compilation of enzymes that have been affirmed as GRAS by FDA for specified or unspecified food uses and listed in 21 CFR Part 184. Conditions for their use are prescribed in the referent regulations and are predicated on the use of nontoxicogenic strains of the respective organisms and on the use of current good manufacturing practice (184.1(b)).

Table 3. Enzyme preparations affirmed as GRAS listed in 21 CFR 184
Section in 21 CFR Description of Enzyme Preparation
§184.1012 Alpha-amylase enzyme preparation from Bacillus stearothermophilus used to hydrolyze edible starch to produce maltodextrin and nutritive carbohydrate sweeteners.
§184.1024 Bromelain derived from pineapples, Ananas comosus and Ananas bracteatus used to hydrolyze proteins and polypeptides.
§184.1027 Mixed carbohydrase and protease enzyme product derived from Bacillus licheniformis for use in hydrolyzing proteins and carbohydrates in the preparation of alcoholic beverages, candy, nutritive sweeteners and protein hydrolysates.
§184.1034 Catalase from bovine liver used to decompose hydrogen peroxide
§184.1316 Ficin (peptide hydrolase) from the genus Ficus to hydrolyze proteins and polypeptides.
§184.1372 Insoluble glucose isomerase enzyme preparations are derived from recognized species of precisely classified, nonpathogenic, and nontoxicogenic microorganisms, including Streptomyces rubiginosus, Actinoplane missouriensis, Streptomyces olivaceus, Streptomyces olivochromogenes and Bacillus coagulans grown in a pure culture fermentation that produces no antibiotic.
§184.1387 Lactase enzyme preparation from Candida pseudotropicalis for use in hydrolyzing lactose to glucose and galactose.
§184.1388 Lactase enzyme preparation from Kluyveromyces lactis (previously called Saccharomyces lactis) for use in hydrolyzing lactose in milk.
§184.1415 Animal lipase (triacylglycerol hydrolase) derived from the edible forestomach of calves, kids or lambs used to hydrolyze fatty acid glycerides.
§184.1420 Lipase enzyme preparation from Rhizopus niveus used in the interesterification of fats and oils.
§184.1443 Malt (α-amylase and β-amylase) from barley to hydrolyze starch.
§184.1583 Pancreatin (peptide hydrolase) from porcine or bovine pancreatic tissue used to hydrolyze proteins or polypeptides.
§184.1585 Papain derived from papaya, Carica papaya L. .
§184.1595 Pepsin (peptide hydrolase) from hog stomach used to hydrolyze proteins.
§184.1685 Rennet (animal derived) and chymosin preparation from Escherichia coli K-12, Kluyveromyces marxianus var. lactis or Aspergillus niger var. awamori to coagulate milk in cheeses and other dairy products.
§184.1914 Trypsin (peptide hydrolase) from porcine or bovine pancreas used to hydrolyze proteins.
§184.1924 Urease enzyme preparation from Lactobacillus fermentum for use in the production of wine.
§184.1985 Aminopeptidase enzyme preparation from Lactococcus lactisused as an optional ingredient for flavor development in the manufacture of cheddar cheese.

The following is a compilation of microbially derived enzymes which the FDA recognized as GRAS in opinion letters issued in the early 1960's. The opinions are predicated on the use of nonpathogenic and nontoxicogenic strains of the respective organisms and on the use of current good manufacturing practice.


Watch the video: ENZYMES REGULATION MECHANISM (October 2022).