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Isomerases
- 2. CLASSIFICATIONOF ENZYME EC 5 : Isomerase EC 6 : Ligase EC 2 : Transferase EC 3 : Hydrolase EC 4 : Lyase EC 1 : Oxidoreductase
- 3. ISOMEARASE ■ Isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. ■ Isomerases belong to the EC 5 primary class of enzymes that catalyze the reactions involving a structural rearrangement of a molecule. ■ The general form of such a reaction is as follows: ■ They convert one isomer to another, meaning that the end product has the same molecular formula but a different physical structure. ■ There is only one substrate yielding one product. https://en.wikipedia.org/wiki/Isomerase https://www.qmul.ac.uk/sbcs/iubmb/enzyme/rules.html
- 4. ■ Isomerases are important biological components of the metabolism and genome of most living organisms. ■ All isomerases have Enzyme Commission numbers beginning in EC 5. ■ Isomerases catalyze reactions across many biological processes, such as in glycolysis and carbohydrate metabolism. ■ According to the type of isomerism, they may be called racemases, epimerases, cis-trans-isomerases, isomerases, tautomerases, mutases or cycloisomerases. Some Examples: • Glucose isomerse • diphosphoglycerate mutase • photo isomerase. • Maleate isomerase https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139 412/
- 5. Racemases, epimerases Cis-trans isomerases Intramolecular oxidoreductase s Intramolecular transferases Intramolecular lyases SUB-CLASS OF ISOMERASE Isomerases are further classified into subclasses: https://www.creative-enzymes.com/resource/Isomerase- Introduction_23.html
- 6. Racemases, epimerases ■ These isomerases invert stereochemistry at the target chiral carbon. ■ Racemases act upon molecules with one chiral carbon whereas epimerases target molecules with multiple chiral carbons. ■ This class is further broken down by the group the enzyme acts upon: ■ This class is further broken down by the group the enzyme acts upon: ■ https://en.wikipedia.org/wiki/Isomerase ■ https://en.wikipedia.org/wiki/Isomerase EC number Description Examples EC 5.1.1 Acting on Amino Acids and Derivative alanine racemase, methionine racemase etc. EC 5.1.2 Acting on Hydroxy Acids and Derivatives lactate racemase, tartrate epimerase etc. EC 5.1.3 Acting on Carbohydrates and Derivatives ribulose-phosphate 3-epimerase, UDP-glucose 4-epimerase etc. EC 5.1.99 Acting on Other Compounds methylmalonyl CoA epimerase, hydantoin racemase etc. https://en.wikipedia.org/wiki/Isomerase
- 7. Acting on Amino Acids and Derivative Acting on Hydroxy Acids and Derivatives EC 5.1.1.1 Accepted name: alanine racemase Reaction: L-alanine = D-alanine Other name(s): L-alanine racemase Systematic name: alanine racemase D- alanine L- alanine EC 5.1.2.1 Accepted name: lactate racemase Reaction: (S)-lactate = (R)-lactate Other name(s): lactico racemase; hydroxyacid racemase; lactic acid racemase Systematic name: lactate racemase Acting on Carbohydrates and Derivatives Acting on Other Compounds EC 5.1.3.1 Accepted name: ribulose-phosphate 3-epimerase Reaction: D-ribulose 5-phosphate = D-xylulose 5- phosphate Other name(s): phosphoribulose epimerase; erythrose-4-phosphate isomerase; pentose-5- phosphate 3-epimerase Systematic name: D-ribulose-5-phosphate 3- EC 5.1.99.1 Accepted name: methyl malonyl-CoA epimerase Reaction: (R)-methyl malonyl-CoA = (S)-methyl malonyl-CoA Other name(s): methyl malonyl-CoA racemase; methyl malonyl coenzyme A racemase; DL-methyl malonyl- CoA racemase Systematic name: methyl malonyl-CoA 2-epimerase https://www.enzyme-database.org
- 8. ■ CIS-TRANS ISOMERISM Also known as geometric isomerism or configurational isomerism. Cis- functional groups are on the same side of the carbon chain. Trans- functional groups are on opposing sides of the carbon chain. https://en.wikipedia.org/wiki/Cis%E2%80%93trans_isomerism
- 9. Cis-Trans Isomerases ■ cis-trans isomerase is a type of isomerase which catalyzes the isomerization of geometric isomers. Example- 1.Photoisomerase- group of enzymes that catalyze the isomerization of photopigments. Rhodopsin is a pigment present in rods of retina. A retinal isomerase is an enzyme that catalyzes the isomerization of trans retinal in eye into 11-cis-retinal which is form suitable to bind with protein opsin. 2.Immunophilins are cellular proteins that display a peptidylprolyl cis–trans isomerase (PPI'ase) enzymatic activity. 3.Cyclophilins are an immunosuppressant which is usually used to suppress rejection after internal organ transplants. These proteins catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues. https://pubmed.ncbi.nlm.nih.gov/1403367/
- 10. ■ INTRAMOLECULAR OXIDOREDUCTASES Enzymes of the isomerase class that catalyze the oxidation of one part of a molecule with a corresponding reduction of another part of the same molecule. Examples: Aldose-Ketose Isomerases; Carbon-Carbon Double Bond Isomerases; Sulfur-Sulfur Bond Isomerases. 1.Aldose-Ketose isomerases- Enzymes that catalyze the interconversion of aldose and ketose compounds EC 5.3.1 Example- Ribose 5 phosphate isomerase- catalyzes the conversion between ribose- 5- phosphate to ribulose- 5- phosphate. Role in calvin cycle and carbohydrate metabolism. http://www.reference.md/files/D019/mD019746.html#:~:text=Definition%3A %20Enzymes%20of%20the%20isomerase,part%20of%20the%20same%2 0molecule.
- 11. 2. Carbon carbon double bond isomerase- Enzymes that catalyze the shifting of a carbon-carbon double bond from one position to another within the same molecule. EC 5.3.3. Example- L-dopachrome isomerase- This enzyme participates in melanogenesis. 3.Sulphur sulphur bond isomerase- Enzymes that catalyze the transposition of a sulfur-sulfur bond. EC 5.3.4. Example- Protein Disulfide-Isomerases- Catalyze the rearrangement of disulfide bonds within proteins during folding. Present in endoplasmic reticulum in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. 4.Keto-enol isomerase- Interconversion of keto and enol forms .EC 5.3.2 Example- Oxaloacetate tautomerase- keto-oxaloacetate enol-oxaloacetate.
- 12. INTRAMOLECULAR TRANSFERASES ■ Enzymes of the isomerase class that catalyze the transfer of acyl-phospho- amino or other groups from one position with in a molecule to another. EXAMPLES: Methylmalonyl-CoA mutase; benzene mutase; phosphogluco mutase; phosphoenolpyruvate mutase; phosphoenolglycerate mutase. 1.Metylmalonyl-CoA mutase – MCM was first identified in rat liver or sheep kidney in 1955. It is a protein that in humans is encoded by MUT gene. This enzyme catalyse the isomerisation of methylmalonyl-CoA to succinyl –CoA, requiring cobalamine in the form of adenosylcobalamine as a cofactor. This reaction is required for the degradation of odd chain fatty chain. The substrate of methymalonyl-CoA mutase, is primerly derived from propionyl-CoA, a substance formed from the catabolism and digestion of valine, threonine, methionine, thymine etc. and the product of enzyme succiyl-CoA.
- 13. 2. Phosphoglucomutase – It is an enzyme that transfers a phosphate group on an α- D – glucose monomer from the one 1 to 6 position in the forward direction or the 6 to 1 position the reverse direction . ■ Role in glycogenesis Phosphoglucomutase also acts in the opposite fashion when blood glucose levels are high. In this case, phosphoglucomutase catalyzes the conversion of glucose 6-phosphate (which is easily generated from glucose by the action of hexokinase) to glucose 1-phosphate.
- 14. INTRAMOLECULAR LYASES This category includes intramolecular lyases. These enzymes catalyze reactions in which a group can be regarded as eliminated from one part of a molecule, leaving a double bond, while remaining covalently attached to the molecule. Some of these catalyzed reactions involve the breaking of a ring structure. Examples: ■ Muconate cycloisomerase : Muconate lactonizing enzymes are involved in the breakdown of lignin-derived aromatics, catechol and protocatechuate, to citric acid cycle intermediates as a part of the β-ketoadipate pathway in soil microbes. The structure of the Muconate lactonizing enzymes (MLEs) consists of a seven-bladed beta propeller with various modifications based on the type of class that it belongs to. MLEs catalyze the bacterial β-ketoadipate pathways by catabolizing aromatic lignin found in plants to intermediates found in the Krebs Cycle. Some MLEs can be halogenated with Cl and perform slightly different functions in the microbe. Halogenated MLEs can remove Cl from halogenated aromatics allowing for the decomposition of 2,4-dichlorophenoxyacetate.
- 15. 2. Inositol-3-phosphate synthase This enzyme belongs to name of this enzyme class is 1D-myo-inositol-3-phosphate of the family of isomerases, specifically the class of intramolecular lyases. The systematic lyase (isomerizing). Other names in common use include myo-inositol-1-phosphate synthase, D-glucose 6- phosphate cycloaldolase, inositol 1-phosphate synthetase, glucose 6-phosphate cyclase, inositol 1-phosphate synthetase, glucose-6-phosphate inositol monophosphate cycloaldolase, glucocycloaldolase, and 1L-myo-inositol-1-phosphate lyase (isomerizing).
- 16. MECHANISMS OF ISOMERASES Different types of isomerases have different action modes such as: ■ Ring expansion and contraction via tautomers The isomerization of glucose (an aldehyde with a six-membered ring) to fructose (a ketone with a five-membered ring) is a classic example of ring opening and contraction catalyzed by an intramolecular oxidoreductase, glucose-6-phosphate isomerase, which involves the ring opening to form an aldose via acid/base catalysis and the formation of a cis-endiol intermediate. Subsequently, a protonated straight-chain ketose is formed and the ring is closed again. https://www.creative-enzymes.com/resource/isomerase- introduction_23.html
- 17. ■ Epimerization The conversion of D-ribulose-5-phosphate into D-xylulose-5-phosphate in the Calvin cycle by ribulose-phosphate 3-epimerase belongs to epimerization, where the substrate and product differ only in stereochemistry at the third carbon in the chain. The deprotonation of that carbon to form a reactive enolate intermediate is likely to be an underlying mechanism, which presents a planar intermediate later gaining the opposite chirality from protonation on the other side. The alliance of these deprotonation-stabilization-protonation steps inverts the stereochemistry at the third carbon. https://www.creative-enzymes.com/resource/isomerase- introduction_23.html
- 18. ■ Intramolecular transfer Chorismate mutase as an intramolecular transferase could catalyze the conversion of chorismate to prephenate that is employed as a precursor for L-tyrosine and L-phenylalanine in some plants and bacteria. Experimental evidence indicates that the isomerase selectively binds the chair transition state, though the exact mechanism of catalysis is not known. It is thought that this binding stabilizes the transition state through electrostatic effects, accounting for the dramatic increase in the reaction rate in the presence of the mutase or upon addition of a specifically-placed cation in the active site. https://www.creative-enzymes.com/resource/isomerase- introduction_23.html
- 19. ■ Intramolecular oxidoreduction Isopentenyl-diphosphate delta isomerase type I (also known as IPP isomerase) is seen in cholesterol synthesis and in particular it catalyzes the conversion of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMAPP). IPP isomerase catalyzes this reaction by the stereoselective antarafacial transposition of a single proton. The double bond is protonated at C4 to form a tertiary carbocation intermediate at C3. The adjacent carbon, C2, is deprotonated from the opposite face to yield a double bond. In effect, the double bond is shifted over. https://www.creative-enzymes.com/resource/isomerase- introduction_23.html C4 C3 C2
- 20. WHERE CAN YOU COME ACROSS THESE ENZYMES? ■ The role of isomerase in human disease: Phosphohexose isomerase deficiency The disease referred to as triosephosphate isomerase deficiency (TPI), is a severe autosomal recessive inherited multisystem disorder of glycolytic metabolism. It is characterized by hemolytic anemia and neurodegeneration, and is caused by anaerobic metabolic dysfunction. This dysfunction results from a missense mutation that effects the encoded TPI protein. TPI deficiency is very rare with less than 50 cases reported in literature. Phosphohexose isomerase deficiency Phosphohexose Isomerase Deficiency (PHI) is also known as phosphoglucose isomerase deficiency or Glucose-6-phosphate isomerase deficiency, and is a hereditary enzyme deficiency. This disease is centered on the glucose-6-phosphate protein. PHI is the result of a dimeric enzyme that catalyzes the reversible interconversion of fructose-6-phosphate and gluose-6-phosphate. In humans deficiency of PHI leads to hemolytic syndrome, which is characterized by a diminished erythrocyte number, lower hematocrit, lower hemoglobin, higher number of reticulocytes and plasma bilirubin concentration, as well as increased liver- and spleen- somatic indices, was exclusively manifested in homozygous mutants.
- 21. ■ Industrial applications In sugar manufacturing is the most common. Glucose isomerase catalyzes the transformation of D-glucose into D-fructose, which is a key part in high-fructose corn syrup production. The efficient isomerization of xylose to xylulose by glucose isomerase is found naturally in bacteria that feed on decaying plant matter. The isomerization of xylose to xylulose has its own commercial applications as interest in biofuels has increased. Its most common industrial use is in the production of ethanol, achieved by the fermentation of xylulose. • Merkle S, Pretsch W (1993). "Glucose-6-phosphate isomerase deficiency associated with nonspherocytic hemolytic anemia in the mouse: an animal model for the human disease" (PDF). Blood. 81 (1): 206– 13. PMID 8417789. • "Triose phosphate isomerase deficiency -TPI" (PDF). Retrieved 26 November 2013. • Bhosale SH, Rao MB, Deshpande VV (Jun 1996). "Molecular and industrial aspects of glucose isomerase". Microbiological Reviews. 60 (2): 280–300. PMC 239444. PMID 8801434