View source for Porphobilinogen synthase

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==Overview==

'''Porphobilinogen synthase''' (or '''ALA dehydratase''', or '''aminolevulinate dehydratase''') synthesizes [[porphobilinogen]] through the asymmetric [[condensation]] of two [[molecules]] of [[aminolevulinic acid]]. All natural [[tetrapyrroles]], including [[heme]]s, [[chlorophyll]]s and [[vitamin B12|vitamin B<sub>12</sub>]], share porphobilinogen as a common precursor.

It catalyzes the second step of the biosynthesis of [[porphyrin]].  The porphobilinogen synthase catalyzed reaction is the first common step in the biosynthesis of all biological tetrapyrroles.

Porphobilinogen synthase is the prototype [[morpheein]].<ref name="Jaffe_Lawrence_2012">{{cite journal | author = Jaffe EK, Lawrence SH | title = Allostery and the dynamic oligomerization of porphobilinogen synthase | journal = Arch. Biochem. Biophys. | volume = 519 | issue = 2 | pages = 144–53 |date=March 2012 | pmid = 22037356 | pmc = 3291741 | doi = 10.1016/j.abb.2011.10.010 }}</ref>

== Structure ==

The structural basis for [[allosteric regulation]] of 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.<ref name="Jaffe_Lawrence_2012"/>

[[File:PBGS Quaternary Structure Equlibrium.jpg|center|alt=PBGS Quaternary Structure Equilibrium.|The PBGS quaternary structure equilibrium includes an inactive hexamer (PDB id 1PV8) that does not have subunit interactions necessary for an ordered active site lid.  Dissociation to the pro-hexamer dimer can be followed by a conformational change that reorients the two αβ-barrel domains to form the pro-octamer dimer.  Association of pro-octamer dimer to octamer (PDB id 1E51) includes formation of subunit interfaces that support order in the active site lid.]]

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 [[Amino acid|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" [[Protein conformation|conformation]] of the active site lid.  The other interaction restricts solvent access from the other end of the αβ-barrel.

In the inactive mulimeric 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 of PBGS ==
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.<ref name="Jaffe_Lawrence_2012"/>

[[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]]''.<ref name="Breinig_2003">{{cite journal | author = Breinig S, Kervinen J, Stith L, Wasson AS, Fairman R, Wlodawer A, Zdanov A, Jaffe EK | title = Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase | journal = Nat. Struct. Biol. | volume = 10 | issue = 9 | pages = 757–63 |date=September 2003 | pmid = 12897770 | doi = 10.1038/nsb963  }}</ref>

====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*).<ref name="pmid19578473">{{cite journal | author = Lawrence SH, Jaffe EK | title = Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching using Morpheeins | journal = Biochem Mol Biol Educ | volume = 36 | issue = 4 | pages = 274–283 | year = 2008 | pmid = 19578473 | pmc = 2575429 | doi = 10.1002/bmb.20211 }}</ref>

== Deficiency == <!--ALA dehydratase deficiency redirects here-->
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.<ref>[http://library.med.utah.edu/NetBiochem/hi32.htm ALA dehydratase reaction], from NetBiochem at the University of Utah. Last modified 1/5/95</ref>

Hereditary insufficiency of porphobilinogen synthase is called [[Aminolevulinic acid dehydratase deficiency porphyria|porphobilinogen synthase (or ALA dehydratase) deficiency poprhyria]]. It is an extremely rare cause of [[porphyria]],<ref name="Jaffe_Stith_2007">{{cite journal | author = Jaffe EK, Stith L | title = ALAD porphyria is a conformational disease | journal = Am. J. Hum. Genet. | volume = 80 | issue = 2 | pages = 329–37 |date=February 2007 | pmid = 17236137 | pmc = 1785348 | doi = 10.1086/511444 }}</ref> with less than 10 cases ever reported.<ref>[http://rarediseasesnetwork.epi.usf.edu/porphyrias/patients/ADP/ Overview of the Porphyrias] at The Porphyrias Consortium (a part of NIH Rare Diseases Clinical Research Network (RDCRN)) Retrieved June 2011</ref>  All disease associated protein variants favor hexamer formation relative to the wild type human enzyme.<ref name="Jaffe_Stith_2007"/>

{|
|[[Image:Heme synthesis.png|center|framed|Heme synthesis&mdash;note that some reactions occur in the [[cytoplasm]] and some in the [[mitochondrion]] (yellow)]]
|}

[[Lead poisoning]] works on the cellular level by binding to this [[enzyme]], rendering it useless.

== 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.<ref name="Jaffe_Lawrence_2012"/>

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 ==
{{reflist|2}}

== External links ==
* {{MeshName|delta-Aminolevulinic+Acid+Dehydratase}}
* http://www.omim.org/entry/125270?search=pbgs&highlight=pbgs

{{Porphyrin biosynthesis enzymes}}
{{Carbon-oxygen lyases}}