Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme () that catalyzes the synthesis of δ-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes, cobalamins and chlorophylls.
The reaction is as follows:
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 and succinyl-CoA. In humans, transcription of ALA synthase is tightly controlled by the presence of Fe<sup>2+</sup>-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.
Enzyme structure and properties
PLP-dependent enzymes are prevalent because they are needed to transform amino acids into other resources. Enzymatic activity varies for different sources of the enzyme. 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.
thumb|center|300px|Heme synthesis
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.
center|framed|Heme synthesis—note that some reactions occur in the [[cytoplasm and some in the mitochondrion (yellow)]]
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.