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Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme (EC 2.3.1.37) that catalyzes the synthesis of D-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes, cobalamins and chlorophylls.^[1] The reaction is as follows:

succinyl-CoA + glycine

\rightleftharpoons

δ-aminolevulinic acid + CoA + CO₂

This 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.

Enzyme structure and properties

PLP-dependent enzymes are prevalent because they are needed to transform amino acids into other resources.^[1] 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.^[1] The protein when extracted from R. spheroids contains 1600-folds and weighs about 80,000 daltons.^[2] Enzymatic activity varies for different sources of the enzyme.^[2]

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 above. 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.^[3]^[4]^[5]^[6] Lysine acts as a general base during this mechanism,.^[1]^[7] In the detailed reaction mechanism, the hydronium atoms that are added in come from a variety of residues in that offer hydrogen bonds to facilitate ALA synthesis.^[1] ALA synthase removes the carboxyl group from glycine and the CoA from the succinyl-CoA by means of its prosthetic group pyridoxal phosphate (a vitamin b6 derivative), forming δ-aminolevulinic acid (dALA), so called because the amino 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 is to facilitate the removal of hydrogen, by utilizing the electrophilic pyridinium 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.^[2] 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.^[2] ALA synthase is also inhibited by hemin and glucose.^[8]

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.

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.^[9] This disease is linked specifically with mutations in the genes that encode for ALAS2.^[9]

References

^ ^a ^b ^c ^d ^e Hunter, Gregory A.; Ferreira, Gloria C. (November 2011). "Molecular enzymology of 5-Aminolevulinate synthase, the gatekeeper of heme biosynthesis". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (11): 1467–1473. doi:10.1016/j.bbapap.2010.12.015. PMC 3090494.
^ ^a ^b ^c ^d Beale, S I (June 1978). "δ-Aminolevulinic Acid in Plants: Its Biosynthesis, Regulation, and Role in Plastid Development". Annual Review of Plant Physiology. 29 (1): 95–120. doi:10.1146/annurev.pp.29.060178.000523.
^ "ALA synthase". flipper e nuvola. Turin University. Retrieved 10 March 2016.
^ "5-Aminolevulinic acid synthase: mechanism, mutations and medicine". Biochim Biophys Acta. 1647 (1–2): 361–6. Apr 2003. doi:10.1016/s1570-9639(03)00095-5. PMID 12686158.
^ CHOI, H (July 2004). "Cloning, expression, and characterization of 5-aminolevulinic acid synthase from Rhodopseudomonas palustris KUGB306". FEMS Microbiology Letters. 236 (2): 175–181. doi:10.1016/j.femsle.2004.05.048.
^ Ferreira, Gloria C.; Neame, Peter J.; Dailey, Harry A. (November 1993). "Heme biosynthesis in mammalian systems: Evidence of a schiff base linkage between the pyridoxal 5′-phosphate cofactor and a lysine residue in 5-aminolevulinate synthase". Protein Science. 2 (11): 1959–1965. doi:10.1002/pro.5560021117. PMC 2142290.
^ Hunter, Gregory A.; Ferreira, Gloria C. (March 1999). "Lysine-313 of 5-Aminolevulinate Synthase Acts as a General Base during Formation of the Quinonoid Reaction Intermediates". Biochemistry. 38 (12): 3711–3718. doi:10.1021/bi982390w.
^ Doss M, Sixel-Dietrich F, Verspohl F (1985). ""Glucose effect" and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatocyte culture: relationship with human acute hepatic porphyrias". J Clin Chem Clin Biochem. 23 (9): 505–13. doi:10.1515/cclm.1985.23.9.505. PMID 4067519.
^ ^a ^b Ajioka, Richard S.; Phillips, John D.; Kushner, James P. (July 2006). "Biosynthesis of heme in mammals". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763 (7): 723–736. doi:10.1016/j.bbamcr.2006.05.005.

External links

NIH
Abu-Farha M, Niles J, Willmore W (2005). "Erythroid-specific 5-aminolevulinate synthase protein is stabilized by low oxygen and proteasomal inhibition". Biochem Cell Biol. 83 (5): 620–30. doi:10.1139/o05-045. PMID 16234850.
Shemin, D; Rittenberg, D (1945). "The Utilization of Glycine for the Synthesis of a Porphyrin". J. Biol. Chem. 159: 567–8.
SIDEROBLASTIC ANEMIAS -ALAS-2 defect disease

UpToDate Contents

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1. ALA脱水酵素欠損性ポルフィリン症ala dehydratase porphyria [show details]
… in mammalian cells. In the liver, for example, the activity of ALAD is 80- to 100-fold that of ALA synthase, the first enzyme in the heme biosynthetic pathway and the rate-limiting enzyme in the liver …
2. ポルフィリン症：概要porphyrias an overview [show details]
…their functions and standard abbreviations. ALA synthase (ALAS) – Converts glycine and succinyl-CoA to ALA (an amino acid). ALA dehydratase (ALAD) – Converts ALA to porphobilinogen (PBG; a pyrrole). PBG …
3. 急性間欠性ポルフィリン症：発症機序、臨床的特徴、診断acute intermittent porphyria pathogenesis clinical features and diagnosis [show details]
… (ubiquitous) form of the first enzyme in the heme biosynthetic pathway, delta-aminolevulinic acid (ALA) synthase (ALAS1), which is the first enzyme in heme synthesis pathway and therefore upstream of PBGD ALAS1 …
4. 遺伝コプロポルフィリン症hereditary coproporphyria [show details]
… to be an increased demand for hepatic heme synthesis and/or induction of the ubiquitous form of ALA synthase (ALAS1) in the liver. Induction of cytochrome P450 enzymes (CYPs, which are heme-containing enzymes) …
5. 鉄芽球性貧血の原因および病態生理causes and pathophysiology of the sideroblastic anemias [show details]
…5-aminolevulinate synthase) was established in several kindreds . The ALAS2 enzyme catalyzes the first and rate-limiting step in heme synthesis (condensation of glycine and succinyl-CoA to ALA) and is essential …

English Journal

Histone acetyltransferase MoHat1 acetylates autophagy-related proteins MoAtg3 and MoAtg9 to orchestrate functional appressorium formation and pathogenicity in .

Yin Z, Chen C, Yang J, Feng W, Liu X, Zuo R, Wang J, Yang L, Zhong K, Gao C, Zhang H, Zheng X, Wang P, Zhang Z.
Autophagy. 2019 Jul;15(7)1234-1257.
Macroautophagy/autophagy is critical for normal appressorium formation and pathogenicity of the rice blast fungus , but the molecular base of autophagy linked to pathogenicity remains elusive in this or other pathogenic fungi. We found that MoHat1, a histone acetyltransferase (HAT) homolog, had a ro
PMID 30776962

Oryza sativa parkeol cyclase. Changes in the substrate folding conformation and the deprotonation sites by mutations at Tyr257: Importance of the hydroxyl group and steric bulk.

Suzuki A, Aikawa Y, Ito R, Hoshino T.
Chembiochem : a European journal of chemical biology. 2019 Jun;().
The Y257 of Oryza sativa parkeol synthase (OsOSC2) corresponds to the H234 of S. cerevisiae lanosterol cyclase (ScLAS), which is proposed to be responsible for the final deprotonation reaction. The Ala mutant afforded nine tetracyclic skeletons as the main products, which consisted of protostadieol
PMID 31180162

Arg-8 of yeast subunit e contributes to the stability of F-ATP synthase dimersand to the generation of the full-conductance megachannel.

Guo L, Carraro M, Carrer A, Minervini G, Urbani A, Masgras I, Tosatto SCE, Szabò I, Bernardi P, Lippe G.
The Journal of biological chemistry. 2019 Jun;().
The mitochondrial F-ATP synthase is a complex molecular motor arranged in V-shaped dimers that is responsible for most cellular ATP synthesis in aerobic conditions. In the yeast F-ATP synthase, subunits e and g of the F sector constitute a lateral domain, which is required for dimer stability and cr
PMID 31160339

Japanese Journal

High-level production of valine by expression of the feedback inhibition-insensitive acetohydroxyacid synthase in Saccharomyces cerevisiae.

Takpho Natthaporn,Watanabe Daisuke,Takagi Hiroshi
2018-03-19
… cerevisiae, valine biosynthesis is regulated by valine itself via the feedback inhibition of acetohydroxyacid synthase (AHAS), which consists of two subunits, the catalytic subunit Ilv2 and the regulatory subunit Ilv6. … Among them, we found that the Asn86Ala, Gly89Asp and Asn104Ala variants resulted in approximately 4-fold higher intracellular valine contents compared with those in cells with the wild-type Ilv6. …
NAID 120006457753

Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences

Yokoyama Yoshihito,Shigeto Tatsuhiko,Miura Rie,Kobayashi Asami,Mizunuma Makito,Yamauchi Aisa,Futagami Masayuki,Mizunuma Hideki
ONCOLOGY LETTERS 13(6), 4933-4938, 2017-06
… Once tumors had developed, 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA) was administered intraperitoneally and the tumor was irradiated twice/week. …
NAID 120006576906

Isolation and characterization of awamori yeast mutants with L-leucine accumulation that overproduce isoamyl alcohol

Takagi Hiroshi,Hashida Keisuke,Watanabe Daisuke [他],Nasuno Ryo,Ohashi Masataka,Iha Tomoya,Nezuo Maiko,Tsukahara Masatoshi
Journal of bioscience and bioengineering 119(2), 140-147, 2015-02
… In yeast, isoamyl alcohol (i-AmOH), known as the key flavor of bread, is mainly produced from α-ketoisocaproate in the pathway of L-leucine biosynthesis, which is regulated by end-product inhibition of α-isopropylmalate synthase (IPMS). … This mutant carried an allele of the LEU4 gene encoding the Ser542Phe/Ala551Val variant IPMS, which is less sensitive to feedback inhibition by L-leucine. …
NAID 110009922496

「ヘム」

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PMC	articles
PubMed	articles
NCBI	proteins

5-aminolevulinate synthase
	Aminolevulinic acid synthase dimer, Rhodobacter capsulatus
Identifiers
EC number	2.3.1.37
CAS number	9037-14-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
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PubMed	articles
NCBI	proteins

　　[★]

英: heme
同: プロトヘム protoheme、フェロプロトポルフィリンIX ferroprotoporphyrin IX
関: ヘマチン hematin

ポルフィリンと鉄イオンの錯体

生合成

→ポルフィリン

反応場所						酵素	補酵素	酵素阻害物質	酵素の障害による疾患
ミトコンドリア	サクシニルCoA succinyl-CoA	グリシン glycine	5-アミノレブリン酸 aminolevulinic acid aminolevulinate ALA	CoA	CO2	5-アミノレブリン酸シンターゼ ALA synthase	ビタミンB6
細胞質	5-アミノレブリン酸 aminolevulinic acid aminolevulinate ALA	←2分子	ポルホビリノゲン porphobilinogen PBG	2H2O		ALA dehydratase		Pb
細胞質	ポルホビリノゲン porphobilinogen PBG		ヒドロキシメチルビラン	4NH3		ウロポルフィリゲノンIシンターゼ uroporphyrinogen I synthase			急性間欠性ポルフィリン症 acute intermittent porphyria
細胞質	ヒドロキシメチルビラン		ウロポルフィリノゲンIII			ウロポルフィリゲノンIIIシンターゼ uroporphyrinogen III synthase
細胞質	ウロポルフィリノゲンIII		コプロポルフィリノゲンIII	4CO2		ウロポルフィリノゲンデカルボキシラーゼ			晩発性皮膚ポルフィリン症 porphyria cutanea tarda
ミトコンドリア	コプロポルフィリノゲンIII		プロトポルフィリノゲンIX	2CO2		コプロポルフィリノゲンオキシダーゼ
ミトコンドリア	プロトポルフィリノゲンIX		プロトポルフィリンIX			プロトポルフィリノゲンオキシダーゼ
ミトコンドリア	プロトポルフィリンIX	Fe2+	ヘム			フェロケラターゼ		Pb

生合成の場所

哺乳類細胞では、赤血球以外は何処でも行われる(ミトコンドリアを有するなら)
実際には、赤血球前駆細胞(erythroid precursor cell)で85%行われており、残りは肝細胞で行われている。

「5-アミノレブリン酸」

　　[★]

英: 5-aminolevulinate 5-aminolevulinic acid , δ-aminolevulinate δ-aminolevulinic acid δ-ALA, aminolevulinate aminolevulinic acid ALA
同: δ-アミノレブリン酸
関: ALA synthase、レブリン酸

構造式：H₂NCH₂COCH₂CH₂COOH

レブリン酸のδ酸素にアミノ基がついた形

概念

ヘム合成の中間体
ミトコンドリアでサクシニルCoAとグリシンからALA synthaseにより5-アミノレブリン酸が生成する。
ミトコンドリアで作成された5-アミノレブリン酸は細胞質に移動
細胞質の2分子の5-アミノレブリン酸はポルホビリノゲンシンターゼによりポルホビリノゲンを生成する。

「synthase」

　　[★]

n.

(脱離酵素リアーゼの逆反応である合成方向の反応を指す) シンターゼ, 合成酵素, 付加酵素

関: lyase、synthetase、transferase

「AL」

　　[★]

「A」

　　[★]

「ALA」

　　[★] 5-アミノレブリン酸 5-aminolevulinate

[mol1-1] Hunter, Gregory A.; Ferreira, Gloria C. (November 2011). "Molecular enzymology of 5-Aminolevulinate synthase, the gatekeeper of heme biosynthesis". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (11): 1467–1473. doi:10.1016/j.bbapap.2010.12.015. PMC 3090494.

[plants-2] Beale, S I (June 1978). "δ-Aminolevulinic Acid in Plants: Its Biosynthesis, Regulation, and Role in Plastid Development". Annual Review of Plant Physiology. 29 (1): 95–120. doi:10.1146/annurev.pp.29.060178.000523.

[3] "ALA synthase". flipper e nuvola. Turin University. Retrieved 10 March 2016.

[4] "5-Aminolevulinic acid synthase: mechanism, mutations and medicine". Biochim Biophys Acta. 1647 (1–2): 361–6. Apr 2003. doi:10.1016/s1570-9639(03)00095-5. PMID 12686158.

[5] CHOI, H (July 2004). "Cloning, expression, and characterization of 5-aminolevulinic acid synthase from Rhodopseudomonas palustris KUGB306". FEMS Microbiology Letters. 236 (2): 175–181. doi:10.1016/j.femsle.2004.05.048.

[6] Ferreira, Gloria C.; Neame, Peter J.; Dailey, Harry A. (November 1993). "Heme biosynthesis in mammalian systems: Evidence of a schiff base linkage between the pyridoxal 5′-phosphate cofactor and a lysine residue in 5-aminolevulinate synthase". Protein Science. 2 (11): 1959–1965. doi:10.1002/pro.5560021117. PMC 2142290.

[7] Hunter, Gregory A.; Ferreira, Gloria C. (March 1999). "Lysine-313 of 5-Aminolevulinate Synthase Acts as a General Base during Formation of the Quinonoid Reaction Intermediates". Biochemistry. 38 (12): 3711–3718. doi:10.1021/bi982390w.

[8] Doss M, Sixel-Dietrich F, Verspohl F (1985). ""Glucose effect" and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatocyte culture: relationship with human acute hepatic porphyrias". J Clin Chem Clin Biochem. 23 (9): 505–13. doi:10.1515/cclm.1985.23.9.505. PMID 4067519.

[heme2-9] Ajioka, Richard S.; Phillips, John D.; Kushner, James P. (July 2006). "Biosynthesis of heme in mammals". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763 (7): 723–736. doi:10.1016/j.bbamcr.2006.05.005.

v t e Transferases: acyltransferases (EC 2.3)
2.3.1: other than amino-acyl groups	acetyltransferases: Acetyl-Coenzyme A acetyltransferase N-Acetylglutamate synthase Choline acetyltransferase Dihydrolipoyl transacetylase Acetyl-CoA C-acyltransferase Beta-galactoside transacetylase Chloramphenicol acetyltransferase N-acetyltransferase Serotonin N-acetyl transferase HGSNAT ARD1A Histone acetyltransferase P300/CBP NAT2 palmitoyltransferases: Carnitine O-palmitoyltransferase CPT1 CPT2 Serine C-palmitoyltransferase SPTLC1 SPTLC2 other: Acyltransferase like 2 Aminolevulinic acid synthase Beta-ketoacyl-ACP synthase Glyceronephosphate O-acyltransferase Lecithin—cholesterol acyltransferase Glycerol-3-phosphate O-acyltransferase 1-acylglycerol-3-phosphate O-acyltransferase 2-acylglycerol-3-phosphate O-acyltransferase ABHD5
2.3.2: Aminoacyltransferases	Gamma-glutamyl transpeptidase Peptidyl transferase Transglutaminase Tissue transglutaminase Keratinocyte transglutaminase Factor XIII
2.3.3: converted into alkyl on transfer	Citrate synthase ATP citrate lyase HMG-CoA synthase Malate synthase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

リンク元	「ヘム」「5-アミノレブリン酸」
関連記事	「synthase」「AL」「A」「ALA」

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案内

案内

ALA synthase