Aminolevulinic acid synthase
Encyclopedia
ALA synthase catalyzes the synthesis of D-Aminolevulinic acid
(ALA) the first common precursor in the biosynthesis of all tetrapyrroles. The enzyme is expressed in all non-plant eukaryotes and the α-class of proteobacteria. Other organisms produce ALA through a three enzyme pathway known as the Shemin pathway. ALA is synthesized through the condensation of glycine
and succinyl-CoA
. In humans, transcription of ALA synthase is tightly controlled by the presence of Fe2+
-binding elements, to prevent accumulation of porphyrin intermediates in the absence of iron. There are two forms of ALA synthase in the body. One form is expressed in red blood cell precursor cells (ALAS2
), whereas the other (ALAS1
) is ubiquitously expressed throughout the body. The red blood cell form is coded by a gene on chromosome x, whereas the other form is coded by a gene on chromosome 3. The disease X-linked sideroblastic anemia
is caused by mutations in the ALA synthase gene on chromosome X, whereas no diseases are known to be caused by mutations in the other gene. Gain of function mutations in the erythroid specific ALA synthase gene have been shown recently to cause a previously unknown form of porphyria known as X-linked-dominant protoporphyria .
ALA synthase removes the carboxyl group from glycine and the CoA
from the succinyl-CoA by means of its prosthetic group pyridoxal phosphate, forming δ-aminolevulinic acid (dALA), so called because the amino group is on the fourth carbon atom in the molecule. Glycine is initially deprotonated by a highly conserved active site lysine, leading to condensation with succinyl-CoA and loss of CoA. Protonation of the carbonyl group of the intermediate by an active site histidine leads to loss of the carboxyl group. The last intermediate is finally reprotonated to produce ALA. Dissociation of ALA from the enzyme is the rate limiting step of the enzymatic reaction and was shown to be depended upon a slow conformational change of the enzyme. The function of pyridoxal phosphate is to facilitate the removal of hydrogen, by utilizing the electrophilic pyridinium
ring as an electron sink.
ALA synthase is inhibited by hemin
and glucose
.
D-Aminolevulinic acid
δ-Aminolevulinic acid is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals and chlorophyll in plants....
(ALA) the first common precursor in the biosynthesis of all tetrapyrroles. The enzyme is expressed in all non-plant eukaryotes and the α-class of proteobacteria. Other organisms produce ALA through a three enzyme pathway known as the Shemin pathway. ALA is synthesized through the condensation of glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
and succinyl-CoA
Succinyl-CoA
Succinyl-Coenzyme A, abbreviated as Succinyl-CoA or SucCoA, is a combination of succinic acid and coenzyme A.-Source:It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation...
. In humans, transcription of ALA synthase is tightly controlled by the presence of Fe2+
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
-binding elements, to prevent accumulation of porphyrin intermediates in the absence of iron. There are two forms of ALA synthase in the body. One form is expressed in red blood cell precursor cells (ALAS2
ALAS2
Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ALAS2 gene. ALAS2 is an aminolevulinic acid synthase....
), whereas the other (ALAS1
ALAS1
Delta-aminolevulinate synthase 1 also known as ALAS1 is a protein that in humans is encoded by the ALAS1 gene. ALAS1 is an aminolevulinic acid synthase....
) is ubiquitously expressed throughout the body. The red blood cell form is coded by a gene on chromosome x, whereas the other form is coded by a gene on chromosome 3. The disease X-linked sideroblastic anemia
Sideroblastic anemia
Sideroblastic anemia or sideroachrestic anemia is a disease in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells . It may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies...
is caused by mutations in the ALA synthase gene on chromosome X, whereas no diseases are known to be caused by mutations in the other gene. Gain of function mutations in the erythroid specific ALA synthase gene have been shown recently to cause a previously unknown form of porphyria known as X-linked-dominant protoporphyria .
ALA synthase removes the carboxyl group from glycine and the CoA
Coenzyme A
Coenzyme A is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
from the succinyl-CoA by means of its prosthetic group pyridoxal phosphate, forming δ-aminolevulinic acid (dALA), so called because the amino group is on the fourth carbon atom in the molecule. Glycine is initially deprotonated by a highly conserved active site lysine, leading to condensation with succinyl-CoA and loss of CoA. Protonation of the carbonyl group of the intermediate by an active site histidine leads to loss of the carboxyl group. The last intermediate is finally reprotonated to produce ALA. Dissociation of ALA from the enzyme is the rate limiting step of the enzymatic reaction and was shown to be depended upon a slow conformational change of the enzyme. The function of pyridoxal phosphate is to facilitate the removal of hydrogen, by utilizing the electrophilic pyridinium
Pyridinium
Pyridinium refers to the cationic form of pyridine. This can either be due to protonation of the ring nitrogen or because of addition of a substituent to the ring nitrogen, typically via alkylation. The lone pair of electrons on the nitrogen atom of pyridine is not delocalized, and thus pyridine...
ring as an electron sink.
ALA synthase is inhibited by hemin
Hemin
Hemin is an iron-containing porphyrin. More specifically, it is Protoporphyrin IX containing a ferric iron ion with a chloride ligand....
and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
.