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== Physiological function of enzyme ALAS2 ==
== Physiological function of enzyme ALAS2 ==
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In vertebrate organisms, there are two genes encoding ALAS enzymes that belong to α-oxoamine synthase family of pyridoxalphosphate(PLP)-dependent enzymes<ref>DOI 10.1146/annurev.biochem.73.011303.074021</ref>. ALAS1 is a house-keeping gene expressed ubiquitously, in contrast ALAS2 (gene location Xp11.21) is specific for erythroid progenitor cells<ref>10.1146/annurev.biochem.73.011303.074021</ref>. Both catalyze initial step in biosynthesis of heme cofactor. While the heme cofactor associated with proteins is essential for several physiological processes, for example transport of oxygen in red blood cells, free heme is toxic and perturbations in its metabolic pathway resulting in accumulation of intermediates lead to various blood diseases<ref>10.1101/cshperspect.a011676</ref> <ref>10.3324/haematol.2013.091991</ref>.
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In vertebrate organisms, there are two genes encoding ALAS enzymes that belong to α-oxoamine synthase family of pyridoxalphosphate(PLP)-dependent enzymes<ref>DOI 10.1146/annurev.biochem.73.011303.074021</ref>. ALAS1 is a house-keeping gene expressed ubiquitously, in contrast ALAS2 (gene location Xp11.21) is specific for erythroid progenitor cells<ref>DOI 10.1146/annurev.biochem.73.011303.074021</ref>. Both catalyze initial step in biosynthesis of heme cofactor. While the heme cofactor associated with proteins is essential for several physiological processes, for example transport of oxygen in red blood cells, free heme is toxic and perturbations in its metabolic pathway resulting in accumulation of intermediates lead to various blood diseases<ref>DOI 10.1101/cshperspect.a011676</ref> <ref>DOI 10.3324/haematol.2013.091991</ref>.
=== ALAS role in heme biosynthesis ===
=== ALAS role in heme biosynthesis ===
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The initial and final steps of 8-step heme biosynthetic pathway take place in the mitochondrial matrix. Since the ALAS mediate first reaction it is rate-limiting enzyme regulating the whole pathway, also known as a gatekeeper<ref>10.1016/j.bbapap.2010.12.015</ref>. It catalyzes PLP-dependent condensation of glycine and succinyl-CoA forming 5-aminolevulinic acid (ALA)<ref>10.1016/S0021-9258(19)77371-2</ref>. ALA is then transported to cytoplasm where it undergoes subsequent reactions and eventually moves back to the mitochondria to form heme<ref>10.1101/cshperspect.a011676</ref>.
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The initial and final steps of 8-step heme biosynthetic pathway take place in the mitochondrial matrix. Since the ALAS mediate first reaction it is rate-limiting enzyme regulating the whole pathway, also known as a gatekeeper<ref>DOI 10.1016/j.bbapap.2010.12.015</ref>. It catalyzes PLP-dependent condensation of glycine and succinyl-CoA forming 5-aminolevulinic acid (ALA)<ref>DOI 10.1016/S0021-9258(19)77371-2</ref>. ALA is then transported to cytoplasm where it undergoes subsequent reactions and eventually moves back to the mitochondria to form heme<ref>DOI 10.1101/cshperspect.a011676</ref>.
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The underlying mechanism of the ALAS enzymatic reaction is induced-fit substrate binding via open-to-close conformational transition. At first, the glycine substrate binds to PLP, an active form of vitamin B6, creating an external aldimine. Following deprotonation of glycine enable nucleophilic attack on the second substrate succinyl-CoA. Consequent condensation and decarboxylation form the ALA product. The product release relies on regeneration of an internal aldimine between PLP and ALAS protein<ref>10.1074/jbc.M609330200</ref>.
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The underlying mechanism of the ALAS enzymatic reaction is induced-fit substrate binding via open-to-close conformational transition. At first, the glycine substrate binds to PLP, an active form of vitamin B6, creating an external aldimine. Following deprotonation of glycine enable nucleophilic attack on the second substrate succinyl-CoA. Consequent condensation and decarboxylation form the ALA product. The product release relies on regeneration of an internal aldimine between PLP and ALAS protein<ref>DOI 10.1074/jbc.M609330200</ref>.
=== Structure of human ALAS2 ===
=== Structure of human ALAS2 ===
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ALAS2 enzyme is an obligatory homodimer. The interface between two monomeric subunits contains two active sites. In the absence of the substrate each active site, specifically its catalytic lysine residue (Lys391), bounds one PLP molecule. There are three domains within one human ALAS2 monomer. That is N-terminal domain (Met1-Val142) which contains mitochondrial targeting sequence, conserved catalytic core (Phe143-Gly544) and C-terminal domain (Leu545-Ala587) which is specific for eukaryotes<ref>10.1016/j.exphem.2012.01.013</ref> <ref>10.1038/s41467-020-16586-x</ref>.
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ALAS2 enzyme is an obligatory homodimer. The interface between two monomeric subunits contains two active sites. In the absence of the substrate each active site, specifically its catalytic lysine residue (Lys391), bounds one PLP molecule. There are three domains within one human ALAS2 monomer. That is N-terminal domain (Met1-Val142) which contains mitochondrial targeting sequence, conserved catalytic core (Phe143-Gly544) and C-terminal domain (Leu545-Ala587) which is specific for eukaryotes<ref>DOI 10.1016/j.exphem.2012.01.013</ref> <ref>DOI 10.1038/s41467-020-16586-x</ref>.
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The conserved catalytic core can be further divided into glycine-rich motif (His219-Ile229) and active site loop (Tyr500-Arg517)<ref>10.1016/j.jbc.2022.101643</ref>. This loop plays a critical role in regulation of product release, since it interacts with the autoinhibitory C-terminal domain forming a regulatory gate . The regulation of the enzyme is further imposed by a particular alpha-helix (Ser568-Phe575) which residues Glu569 and Glu571 form salt bridge network with Asp159 and Arg511 (Figure 1C-D). The network establishes the closed state preventing the transition to the open state, in other words, it blocks the PLP-bounded active site<ref>10.1038/s41467-020-16586-x</ref>.
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The conserved catalytic core can be further divided into glycine-rich motif (His219-Ile229) and active site loop (Tyr500-Arg517)<ref>DOI 10.1016/j.jbc.2022.101643</ref>. This loop plays a critical role in regulation of product release, since it interacts with the autoinhibitory C-terminal domain forming a regulatory gate . The regulation of the enzyme is further imposed by a particular alpha-helix (Ser568-Phe575) which residues Glu569 and Glu571 form salt bridge network with Asp159 and Arg511 (Figure 1C-D). The network establishes the closed state preventing the transition to the open state, in other words, it blocks the PLP-bounded active site<ref>DOI 10.1038/s41467-020-16586-x</ref>.
== Mutations causing blood diseases ==
== Mutations causing blood diseases ==
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=== X-linked sideroblastic anemia ===
=== X-linked sideroblastic anemia ===
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XLSA is the most common form of sideroblastic anemias, because of ALAS2 localization on the X chromosome, the disease is more common in males<ref>10.1111/j.1365-2141.2008.07290.x</ref>. It is caused by various mutations throughout the sequence of ALAS2 enzyme. So far, 91 mutations have been described, mainly in the catalytic core but also in the C-terminal domain<ref>10.1016/j.jbc.2022.101643</ref>. These diverse mutations result in a common phenotype of reduced heme production and iron overload in erythroblasts. The effect of a mutation on ALAS2 varies from protein folding destabilization (e.g., Leu313Pro, Ile324Thr, Gly398Asp), loss-of-function aka decrease in enzymatic activity (e.g., Glu242Lys, Asp263Asn, Pro339Leu, Arg411His), interference with PLP binding site (e.g., Arg170His, Phe259Cys, Asp357Val) to changes in protein-protein interaction (e.g., Met567Val, Ser568Gly)<ref>10.1002/humu.21455</ref> <ref>10.1074/jbc.M111.306423</ref> <ref>10.3324/haematol.2013.095513</ref>.
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XLSA is the most common form of sideroblastic anemias, because of ALAS2 localization on the X chromosome, the disease is more common in males<ref>DOI 10.1111/j.1365-2141.2008.07290.x</ref>. It is caused by various mutations throughout the sequence of ALAS2 enzyme. So far, 91 mutations have been described, mainly in the catalytic core but also in the C-terminal domain<ref>DOI 10.1016/j.jbc.2022.101643</ref>. These diverse mutations result in a common phenotype of reduced heme production and iron overload in erythroblasts. The effect of a mutation on ALAS2 varies from protein folding destabilization (e.g., Leu313Pro, Ile324Thr, Gly398Asp), loss-of-function aka decrease in enzymatic activity (e.g., Glu242Lys, Asp263Asn, Pro339Leu, Arg411His), interference with PLP binding site (e.g., Arg170His, Phe259Cys, Asp357Val) to changes in protein-protein interaction (e.g., Met567Val, Ser568Gly)<ref>DOI 10.1002/humu.21455</ref> <ref>DOI 10.1074/jbc.M111.306423</ref> <ref>DOI 10.3324/haematol.2013.095513</ref>.
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This disease belongs to the group of hemoglobinopathies. It is characterized by microcytic hypochromic anemia and hypochromic anemia with the presence of iron-containing mitochondria surrounding the cell nucleus. These cells are called ring sideroblasts (erythrocyte precursors) and are found in the bone marrow of the patients<ref>10.1002/humu.21455</ref> <ref>10.2147/JBM.S232644</ref>. The patients suffer from mild symptoms such as pallor, fatigue, dizziness, weight loss, heart rate acceleration and more fatal one as cardiac disease and cirrhosis. As a result of secondary toxicity of accumulated iron, diabetes may develop citace. Differential diagnosis requires detection of ring sideroblasts in the bone marrow by iron staining. Next-generation genome sequencing is required to rule out reversible causes<ref>10.2147/JBM.S232644</ref>. Typical treatment for patients with XLSA is pyridoxine supplementation. However, some patients with mutations in PLP-binding site (e.g., Asp357Val) do not respond to pyridoxine treatment. On the other hand, most patients that are responsive to the treatment does not carry PLP-binding site mutations<ref>10.1016/j.jbc.2022.101643</ref>.
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This disease belongs to the group of hemoglobinopathies. It is characterized by microcytic hypochromic anemia and hypochromic anemia with the presence of iron-containing mitochondria surrounding the cell nucleus. These cells are called ring sideroblasts (erythrocyte precursors) and are found in the bone marrow of the patients<ref>DOI 10.1002/humu.21455</ref> <ref>DOI 10.2147/JBM.S232644</ref>. The patients suffer from mild symptoms such as pallor, fatigue, dizziness, weight loss, heart rate acceleration and more fatal one as cardiac disease and cirrhosis. As a result of secondary toxicity of accumulated iron, diabetes may develop citace. Differential diagnosis requires detection of ring sideroblasts in the bone marrow by iron staining. Next-generation genome sequencing is required to rule out reversible causes<ref>DOI 10.2147/JBM.S232644</ref>. Typical treatment for patients with XLSA is pyridoxine supplementation. However, some patients with mutations in PLP-binding site (e.g., Asp357Val) do not respond to pyridoxine treatment. On the other hand, most patients that are responsive to the treatment does not carry PLP-binding site mutations<ref>DOI 10.1016/j.jbc.2022.101643</ref>.
=== X-linked protoporphyria ===
=== X-linked protoporphyria ===
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X-linked protoporphyria is a rare genetic disorder that belongs to the group of photodermatoses<ref>10.1016/j.ymgme.2019.01.020</ref>. It results from a mutation in gene sequence for the C-terminal domain of ALAS2. There are several types of mutations including deletion, missense and frameshift, which cause the protein to be truncated or elongated compared to wild type. One of these mutations (ΔG) is associated with increased stability of the enzyme, while the others cause hyperactivity of the enzyme<ref>10.1016/j.ajhg.2008.08.003</ref> <ref>10.2119/molmed.2013.00003</ref> <ref>10.1093/hmg/dds531</ref>. Deletions result in truncation or frameshift of this autoinhibitory domain disrupt molecular interactions that maintain strict regulation of enzyme activity. The consequence is lower inhibition and thus the aforementioned hyperactivity of the enzyme. Due to the higher activity of ALAS2, toxic heme intermediates accumulate in erythrocytes.
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X-linked protoporphyria is a rare genetic disorder that belongs to the group of photodermatoses<ref>DOI 10.1016/j.ymgme.2019.01.020</ref>. It results from a mutation in gene sequence for the C-terminal domain of ALAS2. There are several types of mutations including deletion, missense and frameshift, which cause the protein to be truncated or elongated compared to wild type. One of these mutations (ΔG) is associated with increased stability of the enzyme, while the others cause hyperactivity of the enzyme<ref>DOI 10.1016/j.ajhg.2008.08.003</ref> <ref>DOI 10.2119/molmed.2013.00003</ref> <ref>DOI 10.1093/hmg/dds531</ref>. Deletions result in truncation or frameshift of this autoinhibitory domain disrupt molecular interactions that maintain strict regulation of enzyme activity. The consequence is lower inhibition and thus the aforementioned hyperactivity of the enzyme. Due to the higher activity of ALAS2, toxic heme intermediates accumulate in erythrocytes.
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The most common symptom of XLP is phototoxicity within minutes after exposure to direct sunlight. It is characterized by burning, itching, tingling, pain and redness of the skin, and blisters may appear rarely, accompanied with swelling and scarring when prolonged sun exposition. Repeated episodes of phototoxicity can lead to permanent and chronic skin changes. Some patients can develop severe symptoms such as enlargement of the spleen and chronic kidney disease. A defect in the heme biosynthetic pathway in those affected leads to the accumulation of protoporphyrin in erythrocytes, which is subsequently released into the plasma and uptaken by the liver and vascular endothelium. The accumulated protoporphyrin becomes activated upon exposure to sunlight and begins to produce singlet oxygen radical reactions that result in tissue damage. Some patients may also develop hepatic dysfunction leading to liver failure due to the deposition of protoporphyrin in bile or hepatocytes. In association with liver failure, some patients may also develop motor neuropathy. In addition, excess protoporphyrin is also linked to the formation of gallstones. Patients with XLP also often suffer from vitamin D deficiency due to sun avoidance<ref>10.1182/blood-2012-05-423186</ref> <ref>10.1016/j.ymgme.2019.01.020</ref>.
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The most common symptom of XLP is phototoxicity within minutes after exposure to direct sunlight. It is characterized by burning, itching, tingling, pain and redness of the skin, and blisters may appear rarely, accompanied with swelling and scarring when prolonged sun exposition. Repeated episodes of phototoxicity can lead to permanent and chronic skin changes. Some patients can develop severe symptoms such as enlargement of the spleen and chronic kidney disease. A defect in the heme biosynthetic pathway in those affected leads to the accumulation of protoporphyrin in erythrocytes, which is subsequently released into the plasma and uptaken by the liver and vascular endothelium. The accumulated protoporphyrin becomes activated upon exposure to sunlight and begins to produce singlet oxygen radical reactions that result in tissue damage. Some patients may also develop hepatic dysfunction leading to liver failure due to the deposition of protoporphyrin in bile or hepatocytes. In association with liver failure, some patients may also develop motor neuropathy. In addition, excess protoporphyrin is also linked to the formation of gallstones. Patients with XLP also often suffer from vitamin D deficiency due to sun avoidance<ref>DOI 10.1182/blood-2012-05-423186</ref> <ref>DOI 10.1016/j.ymgme.2019.01.020</ref>.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

Current revision

ALAS2 in erythroid heme biosynthesis disorders

Enzyme 5’-aminolevulinic acid synthase (ALAS, EC 2.3.1.37) catalyzes the first step in the biosynthesis of heme molecule in alpha-proteobacteria and mitochondria of nonplant eukaryotes. In vertebrates there are two isoforms of the ALAS enzyme. The erythroid-specific ALAS2 located on chromosome X is expressed during erythropoiesis and mediates the biosynthesis of heme that carries oxygen in hemoglobin. Different mutations thorough the sequence of the enzyme lead to two ALAS2-associated blood disorders. Namely X-linked sideroblastic anemia (XLSA, MIM 300751) and X-linked protoporphyria (XLP, MIM 300752) caused typically by loss-of-function (enzyme deficiency) and gain-of-function (enzyme hyperactivity), respectively.

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References

  1. ↑ Eliot AC, Kirsch JF. Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations. Annu Rev Biochem. 2004;73:383-415. doi: 10.1146/annurev.biochem.73.011303.074021. PMID:15189147 doi:http://dx.doi.org/10.1146/annurev.biochem.73.011303.074021
  2. ↑ Eliot AC, Kirsch JF. Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations. Annu Rev Biochem. 2004;73:383-415. doi: 10.1146/annurev.biochem.73.011303.074021. PMID:15189147 doi:http://dx.doi.org/10.1146/annurev.biochem.73.011303.074021
  3. ↑ Dailey HA, Meissner PN. Erythroid heme biosynthesis and its disorders. Cold Spring Harb Perspect Med. 2013 Apr 1;3(4):a011676. doi:, 10.1101/cshperspect.a011676. PMID:23471474 doi:http://dx.doi.org/10.1101/cshperspect.a011676
  4. ↑ Chiabrando D, Mercurio S, Tolosano E. Heme and erythropoieis: more than a structural role. Haematologica. 2014 Jun;99(6):973-83. doi: 10.3324/haematol.2013.091991. PMID:24881043 doi:http://dx.doi.org/10.3324/haematol.2013.091991
  5. ↑ Hunter GA, Ferreira GC. Molecular enzymology of 5-aminolevulinate synthase, the gatekeeper of heme biosynthesis. Biochim Biophys Acta. 2011 Nov;1814(11):1467-73. doi:, 10.1016/j.bbapap.2010.12.015. Epub 2011 Jan 6. PMID:21215825 doi:http://dx.doi.org/10.1016/j.bbapap.2010.12.015
  6. ↑ doi: https://dx.doi.org/10.1016/S0021-9258(19)77371-2
  7. ↑ Dailey HA, Meissner PN. Erythroid heme biosynthesis and its disorders. Cold Spring Harb Perspect Med. 2013 Apr 1;3(4):a011676. doi:, 10.1101/cshperspect.a011676. PMID:23471474 doi:http://dx.doi.org/10.1101/cshperspect.a011676
  8. ↑ Hunter GA, Zhang J, Ferreira GC. Transient kinetic studies support refinements to the chemical and kinetic mechanisms of aminolevulinate synthase. J Biol Chem. 2007 Aug 10;282(32):23025-35. doi: 10.1074/jbc.M609330200. Epub 2007, May 7. PMID:17485466 doi:http://dx.doi.org/10.1074/jbc.M609330200
  9. ↑ Kadirvel S, Furuyama K, Harigae H, Kaneko K, Tamai Y, Ishida Y, Shibahara S. The carboxyl-terminal region of erythroid-specific 5-aminolevulinate synthase acts as an intrinsic modifier for its catalytic activity and protein stability. Exp Hematol. 2012 Jun;40(6):477-86.e1. doi: 10.1016/j.exphem.2012.01.013. Epub, 2012 Jan 21. PMID:22269113 doi:http://dx.doi.org/10.1016/j.exphem.2012.01.013
  10. ↑ Bailey HJ, Bezerra GA, Marcero JR, Padhi S, Foster WR, Rembeza E, Roy A, Bishop DF, Desnick RJ, Bulusu G, Dailey HA Jr, Yue WW. Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release. Nat Commun. 2020 Jun 4;11(1):2813. doi: 10.1038/s41467-020-16586-x. PMID:32499479 doi:http://dx.doi.org/10.1038/s41467-020-16586-x
  11. ↑ Taylor JL, Brown BL. Structural basis for dysregulation of aminolevulinic acid synthase in human disease. J Biol Chem. 2022 Mar;298(3):101643. doi: 10.1016/j.jbc.2022.101643. Epub 2022, Jan 28. PMID:35093382 doi:http://dx.doi.org/10.1016/j.jbc.2022.101643
  12. ↑ Bailey HJ, Bezerra GA, Marcero JR, Padhi S, Foster WR, Rembeza E, Roy A, Bishop DF, Desnick RJ, Bulusu G, Dailey HA Jr, Yue WW. Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release. Nat Commun. 2020 Jun 4;11(1):2813. doi: 10.1038/s41467-020-16586-x. PMID:32499479 doi:http://dx.doi.org/10.1038/s41467-020-16586-x
  13. ↑ Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol. 2008 Oct;143(1):27-38. doi: 10.1111/j.1365-2141.2008.07290.x. Epub, 2008 Jul 14. PMID:18637800 doi:http://dx.doi.org/10.1111/j.1365-2141.2008.07290.x
  14. ↑ Taylor JL, Brown BL. Structural basis for dysregulation of aminolevulinic acid synthase in human disease. J Biol Chem. 2022 Mar;298(3):101643. doi: 10.1016/j.jbc.2022.101643. Epub 2022, Jan 28. PMID:35093382 doi:http://dx.doi.org/10.1016/j.jbc.2022.101643
  15. ↑ Ducamp S, Kannengiesser C, Touati M, Garcon L, Guerci-Bresler A, Guichard JF, Vermylen C, Dochir J, Poirel HA, Fouyssac F, Mansuy L, Leroux G, Tertian G, Girot R, Heimpel H, Matthes T, Talbi N, Deybach JC, Beaumont C, Puy H, Grandchamp B. Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. Hum Mutat. 2011 Jun;32(6):590-7. doi: 10.1002/humu.21455. Epub 2011 Feb 24. PMID:21309041 doi:http://dx.doi.org/10.1002/humu.21455
  16. ↑ Bishop DF, Tchaikovskii V, Hoffbrand AV, Fraser ME, Margolis S. X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the beta-subunit of succinyl-CoA synthetase (SUCLA2). J Biol Chem. 2012 Aug 17;287(34):28943-55. doi: 10.1074/jbc.M111.306423. Epub, 2012 Jun 27. PMID:22740690 doi:http://dx.doi.org/10.1074/jbc.M111.306423
  17. ↑ Liu G, Guo S, Kang H, Zhang F, Hu Y, Wang L, Li M, Ru Y, Camaschella C, Han B, Nie G. Mutation spectrum in Chinese patients affected by congenital sideroblastic anemia and a search for a genotype-phenotype relationship. Haematologica. 2013 Dec;98(12):e158-60. doi: 10.3324/haematol.2013.095513. PMID:24323989 doi:http://dx.doi.org/10.3324/haematol.2013.095513
  18. ↑ Ducamp S, Kannengiesser C, Touati M, Garcon L, Guerci-Bresler A, Guichard JF, Vermylen C, Dochir J, Poirel HA, Fouyssac F, Mansuy L, Leroux G, Tertian G, Girot R, Heimpel H, Matthes T, Talbi N, Deybach JC, Beaumont C, Puy H, Grandchamp B. Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. Hum Mutat. 2011 Jun;32(6):590-7. doi: 10.1002/humu.21455. Epub 2011 Feb 24. PMID:21309041 doi:http://dx.doi.org/10.1002/humu.21455
  19. ↑ Abu-Zeinah G, DeSancho MT. Understanding Sideroblastic Anemia: An Overview of Genetics, Epidemiology, Pathophysiology and Current Therapeutic Options. J Blood Med. 2020 Sep 25;11:305-318. doi: 10.2147/JBM.S232644. eCollection 2020. PMID:33061728 doi:http://dx.doi.org/10.2147/JBM.S232644
  20. ↑ Abu-Zeinah G, DeSancho MT. Understanding Sideroblastic Anemia: An Overview of Genetics, Epidemiology, Pathophysiology and Current Therapeutic Options. J Blood Med. 2020 Sep 25;11:305-318. doi: 10.2147/JBM.S232644. eCollection 2020. PMID:33061728 doi:http://dx.doi.org/10.2147/JBM.S232644
  21. ↑ Taylor JL, Brown BL. Structural basis for dysregulation of aminolevulinic acid synthase in human disease. J Biol Chem. 2022 Mar;298(3):101643. doi: 10.1016/j.jbc.2022.101643. Epub 2022, Jan 28. PMID:35093382 doi:http://dx.doi.org/10.1016/j.jbc.2022.101643
  22. ↑ Balwani M. Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Nov;128(3):298-303. doi: 10.1016/j.ymgme.2019.01.020. Epub , 2019 Jan 24. PMID:30704898 doi:http://dx.doi.org/10.1016/j.ymgme.2019.01.020
  23. ↑ doi: https://dx.doi.org/10.1016/j.ajhg.2008.08.003
  24. ↑ Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria. Mol Med. 2013 Mar 5;19:18-25. doi: 10.2119/molmed.2013.00003. PMID:23348515 doi:http://dx.doi.org/10.2119/molmed.2013.00003
  25. ↑ Ducamp S, Schneider-Yin X, de Rooij F, Clayton J, Fratz EJ, Rudd A, Ostapowicz G, Varigos G, Lefebvre T, Deybach JC, Gouya L, Wilson P, Ferreira GC, Minder EI, Puy H. Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP). Hum Mol Genet. 2013 Apr 1;22(7):1280-8. doi: 10.1093/hmg/dds531. Epub 2012 Dec, 20. PMID:23263862 doi:http://dx.doi.org/10.1093/hmg/dds531
  26. ↑ Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012 Nov 29;120(23):4496-504. doi: 10.1182/blood-2012-05-423186. Epub 2012, Jul 12. PMID:22791288 doi:http://dx.doi.org/10.1182/blood-2012-05-423186
  27. ↑ Balwani M. Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Nov;128(3):298-303. doi: 10.1016/j.ymgme.2019.01.020. Epub , 2019 Jan 24. PMID:30704898 doi:http://dx.doi.org/10.1016/j.ymgme.2019.01.020
  28. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  29. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644

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