Transaldolase
Encyclopedia
Transaldolase is an enzyme
of the non-oxidative phase of the pentose phosphate pathway
. In humans, transaldolase is encoded by the TALDO1 gene
.
The following chemical reaction is catalyzed by transaldolase:
), for reductive biosynthesis, and (2) formation of ribose
which is an essential component of ATP
, DNA
, and RNA
. Transaldolase links the pentose phosphate pathway to glycolysis
. In patients with deficiency of transaldolase, there's an accumulation of erythritol
(from erythrose 4-phosphate
), D-arabitol
, and ribitol
.
The deletion in 3 base pairs in the TALDO1 gene results in the absence of serine at position 171 of the transaldolase protein, which is part of a highly conserved region suggesting that the mutation causes the transaldolase deficiency that is found in erythrocytes and lymphoblast
s. The deletion of this amino acid can lead to liver cirrhosis and hepatosplenomegaly
(enlarged spleen and liver) during early infancy. Transaldolase is also a target of autoimmunity
in patients with multiple sclerosis
.
Transaldolase is a single domain composed of 337 amino acids. The core structure is an α/β barrel, similar to other class I aldolases, made up of eight parallel β-sheets
and seven α-helices
. There are also seven additional α-helices that are not part of the barrel. Hydrophobic amino acids are located between the β-sheets in the barrel and the surrounding α-helices to contribute to packing, such as the area containing Leu-168, Phe-170, Phe-189, Gly-311, and Phe-315. In the crystal, human transaldolase forms a dimer, with the two subunits connected by 18 residues in each subunit. See mechanism to the left for details.
The active site, located in the center of the barrel, contains three key residues: lysine-142, glutamate-106, and aspartate-27. The lysine holds the sugar in place while the glutamate and aspartate act as proton donors and acceptors.
with the keto group in sedoheptulose-7-phosphate after deprotonation by another active site residue, glutamate-106. The reaction mechanism is similar to the reverse reaction catalyzed by aldolase
: the bond joining carbons 3 and 4 is broken, leaving dihydroxyacetone
joined to the enzyme via a Schiff base. This cleavage reaction generates the unusual aldose sugar erythrose-4-phosphate. Then transaldolase catalyzes the condensation of glyceraldehyde-3-phosphate with the Schiff base of dihydroxyacetone
, yielding enzyme bound fructose 6-phosphate
. Hydrolysis of the Schiff base liberates free fructose 6-phosphate
, one of the products of the pentose phosphate pathway.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
of the non-oxidative phase of the pentose phosphate pathway
Pentose phosphate pathway
The pentose phosphate pathway is a process that generates NADPH and pentoses . There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars...
. In humans, transaldolase is encoded by the TALDO1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The following chemical reaction is catalyzed by transaldolase:
- sedoheptulose 7-phosphateSedoheptulose 7-phosphateSedoheptulose 7-phosphate is an intermediate in the pentose phosphate pathway.It is formed by transketolase and acted upon by transaldolase....
+ glyceraldehyde 3-phosphateGlyceraldehyde 3-phosphateGlyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GADP, GAP, TP, GALP or PGAL, is a chemical compound that occurs as an intermediate in several central metabolic pathways of all organisms...
erythrose 4-phosphateErythrose 4-phosphateErythrose 4-phosphate is an intermediate in the pentose phosphate pathway and the Calvin cycle. In addition, it serves as a precursor in the biosynthesis of the aromatic amino acids tyrosine, phenylalanine, and tryptophan....
+ fructose 6-phosphateFructose 6-phosphateFructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
Clinical significance
The pentose phosphate pathway has two metabolic functions: (1) generation of nicotinamide adenine dinucleotide phosphate (reduced NADPHNicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or TPN in older notation , is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent....
), for reductive biosynthesis, and (2) formation of ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
which is an essential component of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. Transaldolase links the pentose phosphate pathway to glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. In patients with deficiency of transaldolase, there's an accumulation of erythritol
Erythritol
Erythritol is a sugar alcohol that has been approved for use as a food additive in the United States and throughout much of the world. It was discovered in 1848 by British chemist John Stenhouse. It occurs naturally in some fruits and fermented foods...
(from erythrose 4-phosphate
Erythrose 4-phosphate
Erythrose 4-phosphate is an intermediate in the pentose phosphate pathway and the Calvin cycle. In addition, it serves as a precursor in the biosynthesis of the aromatic amino acids tyrosine, phenylalanine, and tryptophan....
), D-arabitol
Arabitol
Arabitol or arabinitol is a sugar alcohol. It can be formed by the reduction of either arabinose or lyxose. Some organic acid tests check for the presence of D-arabinitol, which may indicate overgrowth of intestinal parasites such as Candida albicans or other yeast/fungus species....
, and ribitol
Ribitol
Ribitol or adonitol is a crystalline pentose alcohol formed by the reduction of ribose. It occurs naturally in the plant Adonis vernalis, as well as in the cell walls of Gram positive bacteria . It also contributes to the chemical structure of riboflavin.-External links:**...
.
The deletion in 3 base pairs in the TALDO1 gene results in the absence of serine at position 171 of the transaldolase protein, which is part of a highly conserved region suggesting that the mutation causes the transaldolase deficiency that is found in erythrocytes and lymphoblast
Lymphoblast
Lymphoblasts are immature cells which typically differentiate to form mature lymphocytes. Normally lymphoblasts are found in the bone marrow, but in acute lymphoblastic leukemia , lymphoblasts proliferate uncontrollably and are found in large numbers in the peripheral blood.The size is between 10...
s. The deletion of this amino acid can lead to liver cirrhosis and hepatosplenomegaly
Hepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
(enlarged spleen and liver) during early infancy. Transaldolase is also a target of autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
in patients with multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
Structure
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
and seven α-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. There are also seven additional α-helices that are not part of the barrel. Hydrophobic amino acids are located between the β-sheets in the barrel and the surrounding α-helices to contribute to packing, such as the area containing Leu-168, Phe-170, Phe-189, Gly-311, and Phe-315. In the crystal, human transaldolase forms a dimer, with the two subunits connected by 18 residues in each subunit. See mechanism to the left for details.
The active site, located in the center of the barrel, contains three key residues: lysine-142, glutamate-106, and aspartate-27. The lysine holds the sugar in place while the glutamate and aspartate act as proton donors and acceptors.
Mechanism of catalysis
The residue of lysine-142 in the active site of transaldolase forms a Schiff baseSchiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
with the keto group in sedoheptulose-7-phosphate after deprotonation by another active site residue, glutamate-106. The reaction mechanism is similar to the reverse reaction catalyzed by aldolase
Aldolase
Aldolase A is an enzyme that catalyses a reverse aldol reaction: The substrate, fructose 1,6-bisphosphate is broken down into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate . This reaction is a part of glycolysis. Three aldolase isozymes , encoded by three different genes, are...
: the bond joining carbons 3 and 4 is broken, leaving dihydroxyacetone
Dihydroxyacetone
Dihydroxyacetone , or DHA, also known as glycerone, is a simple carbohydrate with formula .DHA is primarily used as an ingredient in sunless tanning products. It is often derived from plant sources such as sugar beets and sugar cane, and by the fermentation of glycerin.-Chemistry:DHA is a...
joined to the enzyme via a Schiff base. This cleavage reaction generates the unusual aldose sugar erythrose-4-phosphate. Then transaldolase catalyzes the condensation of glyceraldehyde-3-phosphate with the Schiff base of dihydroxyacetone
Dihydroxyacetone
Dihydroxyacetone , or DHA, also known as glycerone, is a simple carbohydrate with formula .DHA is primarily used as an ingredient in sunless tanning products. It is often derived from plant sources such as sugar beets and sugar cane, and by the fermentation of glycerin.-Chemistry:DHA is a...
, yielding enzyme bound fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
. Hydrolysis of the Schiff base liberates free fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
, one of the products of the pentose phosphate pathway.