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Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme () that catalyzes the synthesis of
δ-aminolevulinic acid δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in ...
(ALA) the first common precursor in the biosynthesis of all
tetrapyrroles Tetrapyrroles are a class of chemical compounds that contain four pyrrole or pyrrole-like rings. The pyrrole/pyrrole derivatives are linked by ( =- or -- units), in either a linear or a cyclic fashion. Pyrroles are a five-atom ring with four car ...
such as hemes, cobalamins and chlorophylls. The reaction is as follows: :
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate d ...
+
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
\rightleftharpoons
δ-aminolevulinic acid δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in ...
+ CoA + CO2 This enzyme is expressed in all non-plant eukaryotes and the α-class of proteobacteria and the reaction it catalyses is sometimes referred to as the Shemin pathway for ALA formation. Other organisms produce ALA through a three enzyme pathway known as the C5 pathway. ALA is synthesized through the condensation of
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
and
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate d ...
. 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 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. The product of this gene specifies an erythroid-specific mitochondrially located enzyme ...
), 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 Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorpora ...
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.


Enzyme structure and properties

PLP-dependent enzymes are prevalent because they are needed to transform amino acids into other resources. ALAS is a homodimer with similarly sized sub units and the active sites consisting of amino acid side chains such as arginine, threonine, and lysine exist at a subunity interface. The protein when extracted from R. spheroids contains 1600-folds and weighs about 80,000 daltons. Enzymatic activity varies for different sources of the enzyme.


Reaction mechanism

The active sites of ALAS utilize three key amino acid side chains: Arg-85 and Thr-430 and Lys-313. Although these three amino acids have been identified to allow this reaction to proceed, they would be inactive without the addition of cofactor pyridoxal 5’-phosphate (PLP) whose role in this synthesis is detailed in the image below. Before the reaction can begin, the PLP cofactor binds to the lysine side chain to form a Schiff base that promotes attack by glycine substrate. Lysine acts as a general base during this mechanism,. In the detailed reaction mechanism, the hydronium atoms that are added in come from a variety of residues that offer hydrogen bonds to facilitate ALA synthesis. ALA synthase removes the
carboxyl In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
group from glycine and the CoA from the succinyl-CoA by means of its prosthetic group
pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
(a vitamin b6 derivative), forming δ-aminolevulinic acid (dALA), so called because the
amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
group is on the fourth carbon atom in the molecule. This reaction mechanism is particularly unique relative to other enzymes that use the PLP cofactor because 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 Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent ac ...
is to facilitate the removal of hydrogen, by utilizing the electrophilic
pyridinium Pyridinium refers to the cation . It is the conjugate acid of pyridine. Many related cations are known involving substituted pyridines, e.g. picolines, lutidines, collidines. They are prepared by treating pyridine with acids. As pyridine is ...
ring as an electron sink. : The location of this enzyme in biological systems is indicative of the feedback that it may receive. ALA Synthase has been found in bacteria, yeast, avian and mammalian liver and blood cells and bone marrow. The location of this enzyme in animal cells is within the mitochondria. Since the enzyme appears to be located near its source of succinyl-CoA and the end of the heme pathway indicates that the starting and end points of heme biosynthesis serves as feedback for ALA synthase. ALA synthase is also inhibited by
hemin Hemin (haemin; ferric chloride heme) is an iron-containing porphyrin with chlorine that can be formed from a heme group, such as heme B found in the hemoglobin of human blood. Chemistry Hemin is protoporphyrin IX containing a ferric iron (Fe3 ...
and
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
.


Biological function

ALAS1 and ALAS2 catalyze the first step in the process of heme synthesis. It is the first irreversible step and is also rate limiting. This means that the beginning of the formation of hemes is very intentional and subject to a variety of areas of feedback. For example, the two substrates, oxaloacetate and glycine, are highly produced by and utilized in other essential biological processes such as glycolysis and the TCA cycle. The image below illustrates the heme synthesis pathway and the role ALAS plays.


Disease relevance

Aminolevulinic Acid Synthase Deficiency results in a lack of ability to create heme since its job is to catalyze the first step in the process. These deficiencies are often a result of genetic mutation that can result in a variety of diseases. One such disease is x-linked sideroblastic anemia which results in the appearance of red blood cells in the bone marrow. This disease is linked specifically with mutations in the genes that encode for ALAS2.


References


External links


NIH
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