Delta-aminolevulinic acid dehydratase

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"ALAD" redirects here. For the village in Iran, see Alad.
ALAD
Protein ALAD PDB 1e51.png ALADwithZinc 1ylv ALADwithLead 1qnv.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesALAD, ALADH, PBGS, aminolevulinate dehydratase, ALA dehydratase
External IDsOMIM: 125270 MGI: 96853 HomoloGene: 16 GeneCards: ALAD
Orthologs
SpeciesHumanMouse
Entrez

210

17025

Ensembl

ENSG00000148218

ENSMUSG00000028393

UniProt

P13716

P10518

RefSeq (mRNA)

NM_000031
NM_001003945
NM_001317745

NM_001276446
NM_008525

RefSeq (protein)

NP_000022
NP_001003945
NP_001304674

NP_001263375
NP_032551

Location (UCSC)Chr 9: 113.39 – 113.4 MbChr 4: 62.51 – 62.52 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
porphobilinogen synthase
1e51.jpg
DALA dehydratase
Identifiers
EC no.4.2.1.24
CAS no.9036-37-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Delta-aminolevulinic acid dehydratase
Identifiers
SymbolALAD
NCBI gene210
HGNC395
OMIM125270
RefSeqNM_001003945
UniProtP13716
Other data
EC number4.2.1.24
LocusChr. 9 q32
ALAD
PDB 1b4k EBI.jpg
high resolution crystal structure of a mg2-dependent 5-aminolevulinic acid dehydratase
Identifiers
SymbolALAD
PfamPF00490
Pfam clanCL0036
InterProIPR001731
PROSITEPDOC00153
SCOP21aw5 / SCOPe / SUPFAM

Delta-aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme (EC 4.2.1.24) that in humans is encoded by the ALAD gene.[5][6] Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate dehydratase) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen as a common precursor. Porphobilinogen synthase is the prototype morpheein.[7]

Function[]

It catalyzes the following reaction, the second step of the biosynthesis of porphyrin:

2 δ-aminolevulinic acid porphobilinogen + 2 H2O

It therefore catalyzes the condensation of 2 molecules of delta-aminolevulinate to form porphobilinogen (a precursor of heme, cytochromes and other hemoproteins). This reaction is the first common step in the biosynthesis of all biological tetrapyrroles. Zinc is essential for enzymatic activity.

Structure[]

The structural basis for allosteric regulation of Porphobilinogen synthase (PBGS) is modulation of a quaternary structure equilibrium between octamer and hexamer (via dimers), which is represented schematically as 6mer* ↔ 2mer* ↔ 2mer ↔ 8mer. The * represents a reorientation between two domains of each subunit that occurs in the dissociated state because it is sterically forbidden in the larger multimers.[7]

PBGS Quaternary Structure Equilibrium.

PBGS is encoded by a single gene and each PBGS multimer is composed of multiple copies of the same protein. Each PBGS subunit consists of a ~300 residue αβ-barrel domain, which houses the enzyme's active site in its center, and a >25 residue N-terminal arm domain. Allosteric regulation of PBGS can be described in terms of the orientation of the αβ-barrel domain with respect to the N-terminal arm domain.

Each N-terminal arm has up to two interactions with other subunits in a PBGS multimer. One of these interactions helps to stabilize a "closed" conformation of the active site lid. The other interaction restricts solvent access from the other end of the αβ-barrel.

In the inactive multimeric state, the N-terminal arm domain is not involved in the lid-stabilizing interaction, and in the crystal structure of the inactive assembly, the active site lid is disordered.

Allosteric regulators[]

As a nearly universal enzyme with a highly conserved active site, PBGS would not be a prime target for the development of antimicrobials and/or herbicides. To the contrary, allosteric sites can be much more phylogenetically variable than active sites, thus presenting more drug development opportunities.[7]

Phylogenetic variation in PBGS allostery leads to the framing of discussion of PBGS allosteric regulation in terms of intrinsic and extrinsic factors.

Intrinsic allosteric regulators[]

Magnesium[]

The allosteric magnesium ion lies at the highly hydrated interface of two pro-octamer dimers. It appears to be easily dissociable, and it has been shown that hexamers accumulate when magnesium is removed in vitro.[8]

pH[]

Though it is not common to consider hydronium ions as allosteric regulators, in the case of PBGS, side chain protonation at locations other than the active site has been shown to affect the quaternary structure equilibrium, and thus to affect the rate of its catalyzed reaction as well.

Extrinsic allosteric regulators[]

Small molecule hexamer stabilization[]

Inspection of the PBGS 6mer* reveals a surface cavity that is not present in the 8mer. Small molecule binding to this phylogenetically variable cavity has been proposed to stabilize 6mer* of the targeted PBGS and consequently inhibit activity.

Such allosteric regulators are known as morphlocks because they lock PBGS in a specific morpheein form (6mer*).[9]

Lead poisoning[]

ALAD enzymatic activity is inhibited by lead, beginning at blood lead levels that were once considered to be safe (<10 μg/dL) and continuing to correlate negatively across the range from 5 to 95 μg/dL.[10] Inhibition of ALAD by lead leads to anemia primarily because it both inhibits heme synthesis and shortens the lifespan of circulating red blood cells, but also by stimulating the excessive production of the hormone erythropoietin, leading to inadequate maturation of red cells from their progenitors. A defect in the ALAD structural gene can cause increased sensitivity to lead poisoning and acute hepatic porphyria. Alternatively spliced transcript variants encoding different isoforms have been identified.[11]

Deficiency[]

A deficiency of porphobilinogen synthase is usually acquired (rather than hereditary) and can be caused by heavy metal poisoning, especially lead poisoning, as the enzyme is very susceptible to inhibition by heavy metals.[12]

Hereditary insufficiency of porphobilinogen synthase is called porphobilinogen synthase (or ALA dehydratase) deficiency poprhyria. It is an extremely rare cause of porphyria,[13] with less than 10 cases ever reported.[14] All disease associated protein variants favor hexamer formation relative to the wild type human enzyme.[13]

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

PBGS as the prototype morpheein[]

The morpheein model of allostery exemplified by PBGS adds an additional layer of understanding to potential mechanisms for regulation of protein function and complements the increased focus that the protein science community is placing on protein structure dynamics.[7]

This model illustrates how the dynamics of phenomena such as alternate protein conformations, alternate oligomeric states, and transient protein-protein interactions can be harnessed for allosteric regulation of catalytic activity.

References[]

  1. ^ Jump up to: a b c GRCh38: Ensembl release 89: ENSG00000148218 - Ensembl, May 2017
  2. ^ Jump up to: a b c GRCm38: Ensembl release 89: ENSMUSG00000028393 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Eiberg H, Mohr J, Nielsen LS (February 1983). "delta-Aminolevulinatedehydrase: synteny with ABO-AK1-ORM (and assignment to chromosome 9)". Clinical Genetics. 23 (2): 150–4. doi:10.1111/j.1399-0004.1983.tb01864.x. PMID 6839527. S2CID 27267679.
  6. ^ Beaumont C, Foubert C, Grandchamp B, Weil D, Gross MS, Nordmann Y (May 1984). "Assignment of the human gene for delta aminolevulinate dehydrase to chromosome 9 by somatic cell hybridization and specific enzyme immunoassay". Annals of Human Genetics. 48 (2): 153–9. doi:10.1111/j.1469-1809.1984.tb01010.x. PMID 6378062. S2CID 24098976.
  7. ^ Jump up to: a b c d Jaffe EK, Lawrence SH (March 2012). "Allostery and the dynamic oligomerization of porphobilinogen synthase". Archives of Biochemistry and Biophysics. 519 (2): 144–53. doi:10.1016/j.abb.2011.10.010. PMC 3291741. PMID 22037356.
  8. ^ Breinig S, Kervinen J, Stith L, Wasson AS, Fairman R, Wlodawer A, et al. (September 2003). "Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase". Nature Structural Biology. 10 (9): 757–63. doi:10.1038/nsb963. PMID 12897770. S2CID 24188785.
  9. ^ Lawrence SH, Jaffe EK (2008). "Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching using Morpheeins". Biochemistry and Molecular Biology Education. 36 (4): 274–283. doi:10.1002/bmb.20211. PMC 2575429. PMID 19578473.
  10. ^ Abadin H, Ashizawa A, Stevens YW, Llados F, Diamond G, Sage G, Citra M, Quinones A, Bosch SJ, Swarts SG (August 2007). Toxicological Profile for Lead (PDF). Atlanta, GA: Agency for Toxic Substances and Disease Registry (US). pp. 22, 30. PMID 24049859. Retrieved 22 November 2015.
  11. ^ "Entrez Gene: ALAD aminolevulinate, delta-, dehydratase".
  12. ^ ALA dehydratase reaction, from NetBiochem at the University of Utah. Last modified 1/5/95
  13. ^ Jump up to: a b Jaffe EK, Stith L (February 2007). "ALAD porphyria is a conformational disease". American Journal of Human Genetics. 80 (2): 329–37. doi:10.1086/511444. PMC 1785348. PMID 17236137.
  14. ^ Overview of the Porphyrias Archived 2011-07-22 at the Wayback Machine at The Porphyrias Consortium (a part of NIH Rare Diseases Clinical Research Network (RDCRN)) Retrieved June 2011

External links[]

Further reading[]

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