Transferase

Source: Wikipedia, the free encyclopedia.
Not to be confused with Esterase.
RNA polymerase from Saccharomyces cerevisiae complexed with α-Amanitin (in red). Despite the use of the term "polymerase," RNA polymerases are classified as a form of nucleotidyl transferase.[1]

In

biochemical pathways
throughout biology, and are integral to some of life's most important processes.

Transferases are involved in myriad reactions in the cell. Three examples of these reactions are the activity of

acetyl CoA.[5] Transferases are also utilized during translation. In this case, an amino acid chain is the functional group transferred by a peptidyl transferase. The transfer involves the removal of the growing amino acid chain from the tRNA molecule in the A-site of the ribosome and its subsequent addition to the amino acid attached to the tRNA in the P-site.[6]

Mechanistically, an enzyme that catalyzed the following reaction would be a transferase:

In the above reaction (where the dash represents a bond, not a minus sign), X would be the donor, and Y would be the acceptor.

coenzyme
.

History

Some of the most important discoveries relating to transferases occurred as early as the 1930s. Earliest discoveries of transferase activity occurred in other classifications of

beta-galactosidase, protease, and acid/base phosphatase. Prior to the realization that individual enzymes were capable of such a task, it was believed that two or more enzymes enacted functional group transfers.[8]

Biodegradation of dopamine via catechol-O-methyltransferase (along with other enzymes). The mechanism for dopamine degradation led to the Nobel Prize in Physiology or Medicine in 1970.

tracers in 1937.[12][13] This in turn would pave the way for the possibility that similar transfers were a primary means of producing most amino acids via amino transfer.[14]

Another such example of early transferase research and later reclassification involved the discovery of uridyl transferase. In 1953, the enzyme

UDP-glucose pyrophosphorylase was shown to be a transferase, when it was found that it could reversibly produce UTP and G1P from UDP-glucose and an organic pyrophosphate.[15]

Another example of historical significance relating to transferase is the discovery of the mechanism of catecholamine breakdown by catechol-O-methyltransferase. This discovery was a large part of the reason for Julius Axelrod’s 1970 Nobel Prize in Physiology or Medicine (shared with Sir Bernard Katz and Ulf von Euler).[16]

Classification of transferases continues to this day, with new ones being discovered frequently.[17][18] An example of this is Pipe, a sulfotransferase involved in the dorsal-ventral patterning of Drosophila.[19] Initially, the exact mechanism of Pipe was unknown, due to a lack of information on its substrate.[20] Research into Pipe's catalytic activity eliminated the likelihood of it being a heparan sulfate glycosaminoglycan.[21] Further research has shown that Pipe targets the ovarian structures for sulfation.[22] Pipe is currently classified as a Drosophila heparan sulfate 2-O-sulfotransferase.[23]

Nomenclature

L-glutamate is the acceptor, and methyltransferase
is the EC category grouping. This same action by the transferase can be illustrated as follows:

methylamine + L-glutamate
N-methyl-L-glutamate[25]

However, other accepted names are more frequently used for transferases, and are often formed as "acceptor grouptransferase" or "donor grouptransferase." For example, a

nucleotides to the 3’ end of a growing RNA strand.[27] In the EC system of classification, the accepted name for RNA polymerase is DNA-directed RNA polymerase.[28]

Classification

Described primarily based on the type of biochemical group transferred, transferases can be divided into ten categories (based on the EC Number classification).[29] These categories comprise over 450 different unique enzymes.[30] In the EC numbering system, transferases have been given a classification of EC2. Hydrogen is not considered a functional group when it comes to transferase targets; instead, hydrogen transfer is included under oxidoreductases,[30] due to electron transfer considerations.

Classification of transferases into subclasses
EC number Examples Group(s) transferred
EC 2.1
formyltransferase
 single-carbon groups
EC 2.2 transketolase and transaldolase aldehyde or ketone groups
EC 2.3 acyltransferase
alkyl
groups during transfer
EC 2.4 glycosyltransferase, hexosyltransferase, and pentosyltransferase
hexoses and pentoses
EC 2.5 riboflavin synthase and chlorophyll synthase
aryl
groups, other than methyl groups
EC 2.6 transaminase, and oximinotransferase nitrogenous groups
EC 2.7 phosphotransferase, polymerase, and kinase
carboxyl
, etc.)
EC 2.8 sulfurtransferase and sulfotransferase sulfur-containing groups
EC 2.9 selenotransferase selenium-containing groups
EC 2.10 molybdenumtransferase and tungstentransferase molybdenum or tungsten

Role

EC 2.1: single carbon transferases

Reaction involving aspartate transcarbamylase.

EC 2.1 includes enzymes that transfer single-carbon groups. This category consists of transfers of

aspartate
L-carbamoyl aspartate + phosphate.[34]

EC 2.2: aldehyde and ketone transferases

The reaction catalyzed by transaldolase

Enzymes that transfer aldehyde or ketone groups and included in EC 2.2. This category consists of various transketolases and transaldolases.[35] Transaldolase, the namesake of aldehyde transferases, is an important part of the pentose phosphate pathway.[36] The reaction it catalyzes consists of a transfer of a dihydroxyacetone functional group to glyceraldehyde 3-phosphate (also known as G3P). The reaction is as follows: sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate erythrose 4-phosphate + fructose 6-phosphate.[37]

EC 2.3: acyl transferases

Transfer of acyl groups or acyl groups that become alkyl groups during the process of being transferred are key aspects of EC 2.3. Further, this category also differentiates between amino-acyl and non-amino-acyl groups.

peptide bonds during translation.[38] As an aminoacyltransferase, it catalyzes the transfer of a peptide to an aminoacyl-tRNA
, following this reaction: peptidyl-tRNAA + aminoacyl-tRNAB tRNAA + peptidyl aminoacyl-tRNAB.[39]

EC 2.4: glycosyl, hexosyl, and pentosyl transferases

EC 2.4 includes enzymes that transfer

monosaccharides to other molecules.[40] An example of a prominent glycosyltransferase is lactose synthase which is a dimer possessing two protein subunits. Its primary action is to produce lactose from glucose and UDP-galactose.[41]
This occurs via the following pathway: UDP-β-D-galactose + D-glucose UDP + lactose.[42]

EC 2.5: alkyl and aryl transferases

EC 2.5 relates to enzymes that transfer alkyl or aryl groups, but does not include methyl groups. This is in contrast to functional groups that become alkyl groups when transferred, as those are included in EC 2.3. EC 2.5 currently only possesses one sub-class: Alkyl and aryl transferases.[43] Cysteine synthase, for example, catalyzes the formation of acetic acids and cysteine from O3-acetyl-L-serine and hydrogen sulfide: O3-acetyl-L-serine + H2S L-cysteine + acetate.[44]

EC 2.6: nitrogenous transferases

Aspartate aminotransferase can act on several different amino acids

The grouping consistent with transfer of

amino group from one molecule to the other.[46]

The reaction, for example, follows the following order: L-aspartate +2-oxoglutarate oxaloacetate + L-glutamate.[47]

EC 2.7: phosphorus transferases

While EC 2.7 includes enzymes that transfer

activation.[49] Once combined, the CDK-cyclin complex is capable of enacting its function within the cell cycle.[50]

The reaction catalyzed by CDK is as follows: ATP + a target protein ADP + a phosphoprotein.[51]

EC 2.8: sulfur transferases

Ribbon diagram of a variant structure of estrogen sulfotransferase (PDB 1aqy EBI)[52]

Transfer of sulfur-containing groups is covered by EC 2.8 and is subdivided into the subcategories of sulfurtransferases, sulfotransferases, and CoA-transferases, as well as enzymes that transfer alkylthio groups.[53] A specific group of sulfotransferases are those that use PAPS as a sulfate group donor.[54] Within this group is alcohol sulfotransferase which has a broad targeting capacity.[55] Due to this, alcohol sulfotransferase is also known by several other names including "hydroxysteroid sulfotransferase," "steroid sulfokinase," and "estrogen sulfotransferase."[56] Decreases in its activity has been linked to human liver disease.[57] This transferase acts via the following reaction: 3'-phosphoadenylyl sulfate + an alcohol adenosine 3',5'bisphosphate + an alkyl sulfate.[58]

EC 2.9: selenium transferases

EC 2.9 includes enzymes that transfer selenium-containing groups.[59] This category only contains two transferases, and thus is one of the smallest categories of transferase. Selenocysteine synthase, which was first added to the classification system in 1999, converts seryl-tRNA(Sec UCA) into selenocysteyl-tRNA(Sec UCA).[60]

EC 2.10: metal transferases

The category of EC 2.10 includes enzymes that transfer molybdenum or tungsten-containing groups. However, as of 2011, only one enzyme has been added: molybdopterin molybdotransferase.[61] This enzyme is a component of MoCo biosynthesis in Escherichia coli.[62] The reaction it catalyzes is as follows: adenylyl-molybdopterin + molybdate molybdenum cofactor + AMP.[63]

Role in histo-blood group

The A and B transferases are the foundation of the human

antigens.[64] The full name of A transferase is alpha 1-3-N-acetylgalactosaminyltransferase[65] and its function in the cell is to add N-acetylgalactosamine to H-antigen, creating A-antigen.[66]: 55  The full name of B transferase is alpha 1-3-galactosyltransferase,[65] and its function in the cell is to add a galactose molecule to H-antigen, creating B-antigen.[66]

It is possible for

Homo sapiens to have any of four different blood types: Type A (express A antigens), Type B (express B antigens), Type AB (express both A and B antigens) and Type O (express neither A nor B antigens).[67] The gene for A and B transferases is located on chromosome 9.[68] The gene contains seven exons and six introns[69] and the gene itself is over 18kb long.[70] The alleles for A and B transferases are extremely similar. The resulting enzymes only differ in 4 amino acid residues.[66] The differing residues are located at positions 176, 235, 266, and 268 in the enzymes.[66]
: 82–83 

Deficiencies

E. coli
galactose-1-phosphate uridyltransferase. A deficiency of the human isoform of this transferase causes of galactosemia

.

Transferase

illnesses. The most common result of a transferase deficiency is a buildup of a cellular product
.

SCOT deficiency

SCOT deficiency) leads to a buildup of ketones.[71]
ketones leads to intermittent ketoacidosis, which usually first manifests during infancy.[72] Disease sufferers experience nausea, vomiting, inability to feed, and breathing difficulties.[72] In extreme cases, ketoacidosis can lead to coma and death.[72] The deficiency is caused by mutation in the gene OXCT1.[73] Treatments mostly rely on controlling the diet of the patient.[74]

CPT-II deficiency

mitochondria to be processed as a fuel source.[75] The disease is caused by a defect in the gene CPT2.[76] This deficiency will present in patients in one of three ways: lethal neonatal, severe infantile hepatocardiomuscular, and myopathic form.[76] The myopathic is the least severe form of the deficiency and can manifest at any point in the lifespan of the patient.[76] The other two forms appear in infancy.[76] Common symptoms of the lethal neonatal form and the severe infantile forms are liver failure, heart problems, seizures and death.[76] The myopathic form is characterized by muscle pain and weakness following vigorous exercise.[76] Treatment generally includes dietary modifications and carnitine supplements.[76]

Galactosemia

galactose-1-phosphate in the body.[81] Common symptoms include liver failure, sepsis, failure to grow, and mental impairment, among others.[82] Buildup of a second toxic substance, galactitol, occurs in the lenses of the eyes, causing cataracts.[83] Currently, the only available treatment is early diagnosis followed by adherence to a diet devoid of lactose, and prescription of antibiotics for infections that may develop.[84]

Choline acetyltransferase deficiencies

Choline acetyltransferase (also known as ChAT or CAT) is an important enzyme which produces the neurotransmitter acetylcholine.[85] Acetylcholine is involved in many neuropsychic functions such as memory, attention, sleep and arousal.[86][87][88] The enzyme is globular in shape and consists of a single amino acid chain.[89] ChAT functions to transfer an acetyl group from acetyl co-enzyme A to choline in the synapses of nerve cells and exists in two forms: soluble and membrane bound.[89] The ChAT gene is located on chromosome 10.[90]

Alzheimer's disease

Decreased expression of ChAT is one of the hallmarks of Alzheimer's disease.[91] Patients with Alzheimer's disease show a 30 to 90% reduction in activity in several regions of the brain, including the temporal lobe, the parietal lobe and the frontal lobe.[92] However, ChAT deficiency is not believed to be the main cause of this disease.[89]

Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease)

Patients with

symptomatic.[94]

Huntington's disease

Patients with Huntington's also show a marked decrease in ChAT production.[95] Though the specific cause of the reduced production is not clear, it is believed that the death of medium-sized motor neurons with spiny dendrites leads to the lower levels of ChAT production.[89]

Schizophrenia

Patients with Schizophrenia also exhibit decreased levels of ChAT, localized to the

mesopontine tegment of the brain[96] and the nucleus accumbens,[97] which is believed to correlate with the decreased cognitive functioning experienced by these patients.[89]

Sudden infant death syndrome (SIDS)

Recent studies have shown that

respiratory systems.[98]

Congenital myasthenic syndrome (CMS)

presynaptically.[100] These syndromes are characterized by the patients’ inability to resynthesize acetylcholine.[100]

Uses in biotechnology

Terminal transferases

deoxynucleotides in the form of a template to the downstream end or 3'
end of an existing DNA molecule. Terminal transferase is one of the few DNA polymerases that can function without an RNA primer.[101]

Glutathione transferases

The family of glutathione transferases (GST) is extremely diverse, and therefore can be used for a number of biotechnological purposes. Plants use glutathione transferases as a means to segregate toxic metals from the rest of the cell.

transgenic cultigens.[104]

Rubber transferases

Currently the only available commercial source of natural

sunflower.[106] These efforts are focused on sequencing the subunits of the rubber transferase enzyme complex in order to transfect these genes into other plants.[106]

Membrane-associated transferases

Many transferases associate with

transmembrane proteins, for example certain oligosaccharyltransferases or microsomal glutathione S-transferase from MAPEG family
.

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