Non-homologous isofunctional enzymes

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Non-Homologous Isofunctional Enzymes (NISE) are two evolutionarily unrelated enzymes that catalyze the same chemical reaction. Enzymes that catalyze the same reaction are sometimes referred to as analogous as opposed to homologous (Homology (biology)), however it is more appropriate to name them as Non-homologous Isofunctional Enzymes, hence the acronym (NISE). [1] These enzymes all serve the same end function but do so in different organisms without detectable similarity in primary and possibly tertiary structures. [2]

Contents

Background

Enzymes are classified based on recommendations from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology and are given an enzyme commission number, commonly referred to as an EC number. [3] Each distinct enzymatic activity is given a recommended name and EC number. To be classified as a distinct enzyme, "direct experimental evidence is required that the proposed enzyme actually catalyses the reaction claimed" [4]

History

Examples of unrelated enzymes with similar functions were noted as early as 1943 by Warburg and Christian (1943) who discovered two different forms of fructose 1,6-bisphosphate aldolase, one occurring in yeast cells and the other occurring in rabbit muscle. [5] In 1998 an article by Mariana Omelchenko et al, titled Analogous Enzymes: Independent Inventions in Enzyme Evolution [5] identified 105 EC numbers containing two or more proteins without detectable sequence similarity to each other. Of these 105 EC numbers, 34 EC nodes with distinct structural folds were located helping to show independent evolutionary origins. [1] In 2010 another article by Mariana Omelchenko et al, titled Non-homologous isofunctional enzymes: A systematic analysis of alternative solutions in enzyme evolution [1] listed the discovery of 185 distinct EC nodes with only 74 from the original 1998 list, summarizing their twelve year search and concluding that NISE exist for up to 10% of biochemical reactions.

Origins

A possible mechanism for the formation and evolution of these enzymes is recruitment of existing enzymes [6] that gain new functions by a modification in substrate specificity (specifically at or near the active site [7] ) or modification of the existing catalytic mechanism. [5]

Importance

Discovery of NISE can reveal new mechanisms for enzyme catalysis and specific information about biochemical pathways that can be particularly important for drug development. [3]

Examples

A popular example of NISE is the superoxide dismutase family of enzymes which contains three distinct forms (EC 1.15.1.1) [8]

  1. Fe,Mn superoxide dismutase
  2. Cu,Zn superoxide dismutase
  3. Nickel superoxide dismutase

CuZn (SOD1) superoxide dismutase was the first to be discovered and is a homodimer containing copper and zinc, found often in intracellular cytoplasmic spaces. [8] FeMn(SOD2) is a tetramer produced by a leader peptide targeting the manganese containing enzyme only in mitochondrial spaces. [8] Nickel superoxide (SOD3) is the most recently characterized and exists only in extracellular spaces. [8]

Another popular example of NISE are the cellulase family of enzymes, [9] particularly Cellulose 1,4-beta-cellobiosidase also consisting of three distinct forms possessing endonuclease activity. (EC3.2.1.91).

  1. GH-48
  2. GH-7
  3. GH-6

Two classes exist, one class attacks the reducing end of cellulose and the other attacks the non reducing end. GH-6 family enzymes attacks the non reducing end of cellulose while GH-7 family enzymes attack the reducing end. GH-48 family enzymes are bacterial family enzymes only and attack the reducing end of cellulose.

Mechanisms for discovery

Typical genome search methods such as BLAST and the Hidden Markov model are used to find discrepancies and similarities in genomes. [3]

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol, or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Superoxide dismutase</span> Class of enzymes

Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O−
2) anion radical into normal molecular oxygen (O2) and hydrogen peroxide (H
2O
2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive O−
2.

In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula O−2. The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature. Molecular oxygen (dioxygen) is a diradical containing two unpaired electrons, and superoxide results from the addition of an electron which fills one of the two degenerate molecular orbitals, leaving a charged ionic species with a single unpaired electron and a net negative charge of −1. Both dioxygen and the superoxide anion are free radicals that exhibit paramagnetism. Superoxide was historically also known as "hyperoxide".

The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze. As a system of enzyme nomenclature, every EC number is associated with a recommended name for the corresponding enzyme-catalyzed reaction.

<span class="mw-page-title-main">Cellulase</span> Class of enzymes

Cellulase is any of several enzymes produced chiefly by fungi, bacteria, and protozoans that catalyze cellulolysis, the decomposition of cellulose and of some related polysaccharides:

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">SOD2</span> Enzyme

Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the SOD2 gene on chromosome 6. A related pseudogene has been identified on chromosome 1. Alternative splicing of this gene results in multiple transcript variants. This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer.

<span class="mw-page-title-main">Irwin Fridovich</span> American biochemist (1929-2019)

Irwin Fridovich was an American biochemist who, together with his graduate student Joe M. McCord, discovered the enzymatic activity of copper-zinc superoxide dismutase (SOD),—to protect organisms from the toxic effects of superoxide free radicals formed as a byproduct of normal oxygen metabolism. Subsequently, Fridovich's research group also discovered the manganese-containing and the iron-containing SODs from Escherichia coli and the mitochondrial MnSOD (SOD2), now known to be an essential protein in mammals. He spent the rest of his career studying the biochemical mechanisms of SOD and of biological superoxide toxicity, using bacteria as model systems. Fridovich was also Professor Emeritus of Biochemistry at Duke University.

<span class="mw-page-title-main">SOD3</span> Protein-coding gene in the species Homo sapiens

Extracellular superoxide dismutase [Cu-Zn] is an enzyme that in humans is encoded by the SOD3 gene.

<span class="mw-page-title-main">Glycoside hydrolase family 10</span>

In molecular biology, Glycoside hydrolase family 10 is a family of glycoside hydrolases.

<span class="mw-page-title-main">Glycoside hydrolase family 7</span> Enzyme family

In molecular biology, glycoside hydrolase family 7 is a family of glycoside hydrolases EC 3.2.1., which are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycoside hydrolases, based on sequence similarity, has led to the definition of >100 different families. This classification is available on the CAZy web site, and also discussed at CAZypedia, an online encyclopedia of carbohydrate active enzymes.

In molecular biology, glycoside hydrolase family 9 is a family of glycoside hydrolases.

FAD-dependent urate hydroxylase is an enzyme with systematic name urate,NADH:oxygen oxidoreductase . A non-homologous isofunctional enzyme (NISE) to HpxO was found, and named HpyO. HpyO was determined to be a typical Michaelian enzyme. These FAD-dependent urate hydroxylases are flavoproteins.

<span class="mw-page-title-main">Mitochondrial ROS</span> Reactive oxygen species produced by mitochondria

Mitochondrial ROS are reactive oxygen species (ROS) that are produced by mitochondria. Generation of mitochondrial ROS mainly takes place at the electron transport chain located on the inner mitochondrial membrane during the process of oxidative phosphorylation. Leakage of electrons at complex I and complex III from electron transport chains leads to partial reduction of oxygen to form superoxide. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by two dismutases including superoxide dismutase 2 (SOD2) in mitochondrial matrix and superoxide dismutase 1 (SOD1) in mitochondrial intermembrane space. Collectively, both superoxide and hydrogen peroxide generated in this process are considered as mitochondrial ROS.

<span class="mw-page-title-main">Nickel superoxide dismutase</span>

Nickel superoxide dismutase (Ni-SOD) is a metalloenzyme that, like the other superoxide dismutases, protects cells from oxidative damage by catalyzing the disproportionation of the cytotoxic superoxide radical to hydrogen peroxide and molecular oxygen. Superoxide is a reactive oxygen species that is produced in large amounts during photosynthesis and aerobic cellular respiration. The equation for the disproportionation of superoxide is shown below:

<span class="mw-page-title-main">CCS (gene)</span> Protein-coding gene in the species Homo sapiens

Copper chaperone for superoxide dismutase is a metalloprotein that is responsible for the delivery of Cu to superoxide dismutase (SOD1). CCS is a 54kDa protein that is present in mammals and most eukaryotes including yeast. The structure of CCS is composed of three distinct domains that are necessary for its function. Although CCS is important for many organisms, there are CCS independent pathways for SOD1, and many species lack CCS all together, such as C. elegans. In humans the protein is encoded by the CCS gene.

<span class="mw-page-title-main">Superoxide dismutase mimetics</span> Synthetic compounds

Superoxide dismutase (SOD) mimetics are synthetic compounds that mimic the native superoxide dismutase enzyme. SOD mimetics effectively convert the superoxide anion, a reactive oxygen species, into hydrogen peroxide, which is further converted into water by catalase. Reactive oxygen species are natural byproducts of cellular respiration and cause oxidative stress and cell damage, which has been linked to causing cancers, neurodegeneration, age-related declines in health, and inflammatory diseases. SOD mimetics are a prime interest in therapeutic treatment of oxidative stress because of their smaller size, longer half-life, and similarity in function to the native enzyme.

Evolution of metal ions in biological systems refers to the incorporation of metallic ions into living organisms and how it has changed over time. Metal ions have been associated with biological systems for billions of years, but only in the last century have scientists began to truly appreciate the scale of their influence. Major and minor metal ions have become aligned with living organisms through the interplay of biogeochemical weathering and metabolic pathways involving the products of that weathering. The associated complexes have evolved over time.

<span class="mw-page-title-main">Iron superoxide dismutase</span> Enzyme that catalyses reduction of superoxides

Iron superoxide dismutase (FeSOD) is a metalloenzyme that belongs to the superoxide dismutases family of enzymes. Like other superoxide dismutases, it catalyses the dismutation of superoxides into diatomic oxygen and hydrogen peroxide. Found primarily in prokaryotes such as Escherichia coli and present in all strict anaerobes, examples of FeSOD have also been isolated from eukaryotes, such as Vigna unguiculata.

References

  1. 1 2 3 Omelchenko, Marina V.; Galperin, Michael Y.; Wolf, Yuri I.; Koonin, Eugene V. (2010). "Non-homologous isofunctional enzymes: A systematic analysis of alternative solutions in enzyme evolution". Biology Direct. 5: 31. doi: 10.1186/1745-6150-5-31 . PMC   2876114 . PMID   20433725.
  2. ↑ Gomes, Monete Rajão; Guimarães, Ana Carolina Ramos; De Miranda, Antonio Basílio (2011). "Specific and Nonhomologous Isofunctional Enzymes of the Genetic Information Processing Pathways as Potential Therapeutical Targets for Tritryps". Enzyme Research. 2011: 1–8. doi: 10.4061/2011/543912 . PMC   3145330 . PMID   21808726.
  3. 1 2 3 Otto, Thomas D.; Guimaraes, Ana Carolina R.; Degrave, Wim M.; De Miranda, Antonio B. (2008). "AnEnPi: identification and annotation of analogous enzymes". BMC Bioinformatics. 9: 544. doi: 10.1186/1471-2105-9-544 . PMC   2628392 . PMID   19091081.
  4. ↑ "Enzyme Nomenclature". www.sbcs.qmul.ac.uk. Retrieved 2017-12-01.
  5. 1 2 3 Galperin, Michael Y.; Walker, D. Roland; Koonin, Eugene V. (1998). "Analogous Enzymes: Independent Inventions in Enzyme Evolution". Genome Research. 8 (8): 779–790. doi: 10.1101/gr.8.8.779 . PMID   9724324.
  6. ↑ Foster, Jeremy M.; Davis, Paul J.; Raverdy, Sylvine; Sibley, Marion H.; Raleigh, Elisabeth A.; Kumar, Sanjay; Carlow, Clotilde K. S. (2010). "Evolution of Bacterial Phosphoglycerate Mutases: Non-Homologous Isofunctional Enzymes Undergoing Gene Losses, Gains and Lateral Transfers". PLOS ONE. 5 (10): e13576. Bibcode:2010PLoSO...513576F. doi: 10.1371/journal.pone.0013576 . PMC   2964296 . PMID   21187861.
  7. ↑ Galperin, Michael Y.; Koonin, Eugene V. (2012). "Divergence and Convergence in Enzyme Evolution". Journal of Biological Chemistry. 287 (1): 21–28. doi: 10.1074/jbc.R111.241976 . PMC   3249071 . PMID   22069324.
  8. 1 2 3 4 Zelko, Igor N.; Mariani, Thomas J.; Folz, Rodney J. (2002). "Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression". Free Radical Biology and Medicine. 33 (3): 337–349. doi:10.1016/S0891-5849(02)00905-X. PMID   12126755.
  9. ↑ Sukharnikov, Leonid O.; Cantwell, Brian J.; Podar, Mircea; Zhulin, Igor B. (2011). "Cellulases: Ambiguous nonhomologous enzymes in a genomic perspective". Trends in Biotechnology. 29 (10): 473–479. doi:10.1016/j.tibtech.2011.04.008. PMC   4313881 . PMID   21683463.
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