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In biochemistry, isomerases are a general class of that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which chemical bond are Bond cleavage and formed. The general form of such a reaction is as follows:
There is only one substrate yielding one product. This product has the same chemical formula as the substrate but differs in bond connectivity or spatial arrangement. Isomerases catalyze reactions across many biological processes, such as in glycolysis and carbohydrate metabolism.
Stereoisomers have the same ordering of individual bonds and the same connectivity but the three-dimensional arrangement of bonded atoms differ. For example, 2-butene exists in two isomeric forms: cis-2-butene and trans-2-butene. The sub-categories of isomerases containing racemases, epimerases and cis-trans isomers are examples of enzymes catalyzing the interconversion of stereoisomers. Intramolecular lyases, oxidoreductases and transferases catalyze the interconversion of structural isomers.
The prevalence of each isomer in nature depends in part on the isomerization energy, the difference in energy between isomers. Isomers close in energy can interconvert easily and are often seen in comparable proportions. The isomerization energy, for example, for converting from a stable cis isomer to the less stable trans isomer is greater than for the reverse reaction, explaining why in the absence of isomerases or an outside energy source such as ultraviolet radiation a given cis isomer tends to be present in greater amounts than the trans isomer. Isomerases can increase the reaction rate by lowering the isomerization energy. (2025). 9780763721978, Jones and Bartlett. ISBN 9780763721978
Calculating isomerase enzyme kinetics from experimental data can be more difficult than for other enzymes because the use of product inhibition experiments is impractical. That is, isomerization is not an irreversible reaction since a reaction vessel will contain one substrate and one product so the typical simplified model for calculating reaction kinetics does not hold. There are also practical difficulties in determining the rate-determining step at high concentrations in a single isomerization. Instead, tracer perturbation can overcome these technical difficulties if there are two forms of the unbound enzyme. This technique uses isotope exchange to measure indirectly the interconversion of the free enzyme between its two forms. The radiolabeled substrate and product diffusion in a time-dependent manner. When the system reaches equilibrium the addition of unlabeled substrate perturbs or unbalances it. As equilibrium is established again, the radiolabeled substrate and product are tracked to determine energetic information.
The earliest use of this technique elucidated the kinetics and mechanism underlying the action of phosphoglucomutase, favoring the model of indirect transfer of phosphate with one intermediate and the direct transfer of glucose. This technique was then adopted to study the profile of proline racemase and its two states: the form which isomerizes L-proline and the other for D-proline. At high concentrations it was shown that the transition state in this interconversion is rate-limiting and that these enzyme forms may differ just in the protonation at the and basic functional group of the active site.
| + Racemases and epimerases: ! EC number | Examples |
| alanine racemase, methionine racemase | |
| lactate racemase, tartrate epimerase | |
| ribulose-phosphate 3-epimerase, UDP-glucose 4-epimerase | |
| methylmalonyl CoA epimerase, hydantoin racemase | |
This category is not broken down any further. All entries presently include:
| + Cis-trans isomerases: ! EC number | Examples |
| Maleate isomerase | |
| Maleylacetoacetate isomerase | |
| Maleylpyruvate isomerase | |
| Linoleate isomerase | |
| Furylfuramide isomerase | |
| Peptidylprolyl isomerase | |
| Farnesol 2-isomerase | |
| 2-chloro-4-carboxymethylenebut-2-en-1,4-olide isomerase | |
| Zeta-carotene isomerase | |
| Prolycopene isomerase | |
| Beta-carotene isomerase | |
| + Intramolecular oxidoreductases: ! EC number | Examples |
| Triose-phosphate isomerase, Ribose-5-phosphate isomerase | |
| Phenylpyruvate tautomerase, Oxaloacetate tautomerase | |
| Steroid Delta-isomerase, L-dopachrome isomerase | |
| Protein disulfide-isomerase | |
| Prostaglandin-D synthase, Allene-oxide cyclase | |
| + Intramolecular transferases: ! EC number | Examples |
| Lysolecithin acylmutase, Precorrin-8X methylmutase | |
| Phosphoglucomutase, Phosphopentomutase | |
| Beta-lysine 5,6-aminomutase, Tyrosine 2,3-aminomutase | |
| (hydroxyamino)benzene mutase, Isochorismate synthase | |
| Methylaspartate mutase, Chorismate mutase | |
This category is not broken down any further. All entries presently include:
| + Intramolecular lyases: ! EC number | Examples |
| Muconate cycloisomerase | |
| 3-carboxy-cis,cis-muconate cycloisomerase | |
| Tetrahydroxypteridine cycloisomerase | |
| Inositol-3-phosphate synthase | |
| Carboxy-cis,cis-muconate cyclase | |
| Chalcone isomerase | |
| Chloromuconate cycloisomerase | |
| (+)-bornyl diphosphate synthase | |
| Cycloeucalenol cycloisomerase | |
| Alpha-pinene-oxide decyclase | |
| Dichloromuconate cycloisomerase | |
| Copalyl diphosphate synthase | |
| Ent-copalyl diphosphate synthase | |
| Syn-copalyl-diphosphate synthase | |
| Terpentedienyl-diphosphate synthase | |
| Halimadienyl-diphosphate synthase | |
| (S)-beta-macrocarpene synthase | |
| Lycopene epsilon-cyclase | |
| Lycopene beta-cyclase | |
| Prosolanapyrone-III cycloisomerase | |
| D-ribose pyranase | |
Glucose-6-phosphate first binds to the active site of the isomerase. The isomerase opens the ring: its histidine residue protonation the oxygen on the glucose ring (and thereby breaking the O5-C1 bond) in conjunction with lysine deprotonating the C1 hydroxyl oxygen. The ring opens to form a straight-chain aldose with an acidic C2 proton. The C3-C4 bond rotates and glutamic acid (assisted by His388) depronates C2 to form a double bond between C1 and C2. A enol intermediate is created and the C1 oxygen is protonated by the catalytic residue, accompanied by the deprotonation of the endiol C2 oxygen. The straight-chain ketose is formed. To close the fructose ring, the reverse of ring opening occurs and the ketose is protonated.
PHI is a very rare disease with only 50 cases reported in literature to date.
Diagnosis is made on the basis of the clinical picture in association with biochemical studies revealing erythrocyte GPI deficiency (between 7 and 60% of normal) and identification of a mutation in the GPI gene by molecular analysis.
The deficiency of phosphohexose isomerase can lead to a condition referred to as hemolytic syndrome. As in humans, the 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.
TPI deficiency is very rare with less than 50 cases reported in literature. Being an autosomal recessive inherited disease, TPI deficiency has a 25% recurrence risk in the case of heterozygous parents. It is a congenital disease that most often occurs with hemolytic anemia and manifests with jaundice. Most patients with TPI for Glu104Asp mutation or heterozygous for a TPI null allele and Glu104Asp have a life expectancy of infancy to early childhood. TPI patients with other mutations generally show longer life expectancy. There are only two cases of individuals with TPI living beyond the age of 6. These cases involve two brothers from Hungary, one who did not develop neurological symptoms until the age of 12, and the older brother who has no neurological symptoms and suffers from anemia only.
Individuals with TPI show obvious symptoms after 6–24 months of age. These symptoms include: dystonia, tremor, dyskinesia, pyramidal tract signs, cardiomyopathy and spinal motor neuron involvement. Patients also show frequent respiratory system bacterial infections.
TPI is detected through deficiency of enzymatic activity and the build-up of dihyroxyacetone phosphate(DHAP), which is a toxic substrate, in erythrocytes. This can be detected through physical examination and a series of lab work. In detection, there is generally myopathic changes seen in muscles and chronic axonal neuropathy found in the nerves. Diagnosis of TPI can be confirmed through molecular genetics. Chorionic villus DNA analysis or analysis of fetal red cells can be used to detect TPI in antenatal diagnosis.
Treatment for TPI is not specific, but varies according to different cases. Because of the range of symptoms TPI causes, a team of specialist may be needed to provide treatment to a single individual. That team of specialists would consists of pediatricians, cardiologists, neurologists, and other healthcare professionals, that can develop a comprehensive plan of action.
Supportive measures such as red cell transfusions in cases of severe anaemia can be taken to treat TPI as well. In some cases, spleen removal (splenectomy) may improve the anaemia. There is no treatment to prevent progressive neurological impairment of any other non-haematological clinical manifestation of the diseases.
The conversion of glucose to fructose is a key component of high-fructose corn syrup production. Isomerization is more specific than older chemical methods of fructose production, resulting in a higher yield of fructose and no By-product. The fructose produced from this isomerization reaction is purer with no residual flavors from Contamination. High-fructose corn syrup is preferred by many confectionery and soda manufacturers because of the high sweetening power of fructose (twice that of sucrose), its relatively low cost and its inability to crystallize. Fructose is also used as a sweetener for use by diabetics. Major issues of the use of glucose isomerase involve its inactivation at higher temperatures and the requirement for a high pH (between 7.0 and 9.0) in the reaction environment. Moderately high temperatures, above 70 °C, increase the yield of fructose by at least half in the isomerization step. The enzyme requires a divalent ion such as cobalt and magnesium for peak activity, an additional cost to manufacturers. Glucose isomerase also has a much higher affinity for xylose than for glucose, necessitating a carefully controlled environment.
The isomerization of xylose to xylulose has its own commercial applications as interest in has increased. This reaction is often seen naturally in Detritivore that feed on decaying plant matter. Its most common industrial use is in the production of ethanol, achieved by the fermentation of xylulose. The use of hemicellulose as source material is very common. Hemicellulose contains xylan, which itself is composed of xylose in Glycosidic bond. The use of glucose isomerase very efficiently converts xylose to xylulose, which can then be acted upon by fermenting yeast. Overall, extensive research in genetic engineering has been invested into optimizing glucose isomerase and facilitating its recovery from industrial applications for re-use.
Glucose isomerase is able to catalyze the isomerization of a range of other sugars, including D-ribose, D-allose and L-arabinose. The most efficient substrates are those similar to glucose and xylose, having equatorial hydroxyl groups at the third and fourth carbons. The current model for the mechanism of glucose isomerase is that of a hydride shift based on X-ray crystallography and isotope exchange studies.
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