Sandbox Reserved 349: Difference between revisions
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{{STRUCTURE_3eq1 | PDB=3eq1 | SCENE= }} | {{STRUCTURE_3eq1 | PDB=3eq1 | SCENE= }} | ||
Porphobilinogen deaminase (PBGD) also known as Hydroxymethylbilane synthase, is a monomeric | Porphobilinogen deaminase (PBGD) also known as Hydroxymethylbilane synthase, is a monomeric deaminase and is the third enzyme in the heme biosynthesis pathways in mammals<ref name="Raj">PMID: 19207107</ref>. It catalyses the polymerization of four porphobilinogen molecules to yield hydroxymethylbilane, a precursor in the formation of [[Porphyrin]]<ref name="Peter">PMID:3079571</ref>. Porphobilinogen deaminases are able to form surprisingly stable enzyme-substrate complexes with up to four pyrrole substrates interacting with the active site, a feature unique to the group of enzymes<ref name="Anderson">PMID:7354069</ref>. <scene name='Sandbox_Reserved_349/Dpm/3'>Dipyrromethane (DPM)</scene>, a cofactor unique to porphobilinogen deaminases, is thought to stabilize these interactions at each of the two active domains<ref name="Peter">PMID:3079571</ref>. Mutations in the human PBGD (hPBGD) gene are responsible for the condition Acute Intermittent Porphyria (AIP) in humans<ref name="Raj">PMID: 19207107</ref>. | ||
=Porphobilinogen deaminase= | =Porphobilinogen deaminase= | ||
__TOC__ | __TOC__ | ||
==Structure== | ==Structure== | ||
<Structure load='3eq1' size='250' frame='true' align='left' scene='Sandbox_Reserved_349/Dpm/3' /> | <Structure load='3eq1' size='250' frame='true' align='left' scene='Sandbox_Reserved_349/Dpm/3' /> | ||
PBGD is a monomeric three-domain polypeptide with each domain consisting of approximately 110 amino acids. The human variant has an additional 29 residue loop in domain three that extends hydrogen bonding across domains one and three while ''E.coli'' PBGD is lacking this extended loop <ref name="Raj">PMID: 19207107</ref>. In the active site, a unique molecule known as <scene name='Sandbox_Reserved_349/Dpm/3'>Dipyrromethane</scene> interacts with porphobilinogen and anchors it in place<ref name="Raj">PMID: 19207107</ref>. Ordered <scene name='Sandbox_Reserved_349/So4_hbond/1'>sulfate ions</scene> are also hydrogen bonded with Arg26 and Ser28 residues near the active site that are highly conserved amongst human and ''E.coli'' variants of PBGD<ref name="Raj">PMID: 19207107</ref>. | PBGD is a monomeric three-domain polypeptide with each domain consisting of approximately 110 amino acids. The human variant has an additional 29 residue loop in domain three that extends hydrogen bonding across domains one and three while ''E.coli'' PBGD is lacking this extended loop <ref name="Raj">PMID: 19207107</ref>. In the active site, a unique molecule known as <scene name='Sandbox_Reserved_349/Dpm/3'>Dipyrromethane</scene> interacts with porphobilinogen and anchors it in place<ref name="Raj">PMID: 19207107</ref>. DPM consists of two pyrole units disulfide-bound to CYS[242]<ref > A.R. Battersby, F.J. Leeper. Biosynthesis of the pigments of life: mechanistic studies on the conversion of porphobilinogen to uroporphyrinogen III. Chern. Rev. 1990 Nov;90(7):1261-1274</ref>. Ordered <scene name='Sandbox_Reserved_349/So4_hbond/1'>sulfate ions</scene> are also hydrogen bonded with Arg26 and Ser28 residues near the active site that are highly conserved amongst human and ''E.coli'' variants of PBGD<ref name="Raj">PMID: 19207107</ref>. | ||
Although PBGD appears to have hydrogen bonding capabilities between two identical PBGD units, at physiological pH, these interactions account for a dimer interface of approximately 5% while average dimer interface between subunits is 16%<ref name="Raj">PMID: 19207107</ref>. Therefore, it is generally assumed that this protein is active naturally as a monomeric enzyme, while the crystalline form is a homo-dimeric structure of two identical PBGD subunits<ref name="Raj">PMID: 19207107</ref>. | Although PBGD appears to have hydrogen bonding capabilities between two identical PBGD units, at physiological pH, these interactions account for a dimer interface of approximately 5% while average dimer interface between subunits is 16%<ref name="Raj">PMID: 19207107</ref>. Therefore, it is generally assumed that this protein is active naturally as a monomeric enzyme, while the crystalline form is a homo-dimeric structure of two identical PBGD subunits<ref name="Raj">PMID: 19207107</ref>. | ||
== | ==Mechanism== | ||
=== | PBGD is responsible for the formation of hydroxymethylbilane (HMB) from four porphobilinogen (PBG) subunits<ref name="Peter">PMID:3079571</ref>. The enzyme is loaded with a single porphobilinogen that is covalently linked to the dipyrromethane cofactor<ref name="Lander">PMID: 2025226</ref>. The remaining three PBG units are attached in a head-to-tail fashion to yield an early, linear, HMB precursor that is covalently linked to PBGD<ref name="Lander">PMID: 2025226</ref>. | ||
==Importance of hPBGD== | ==Importance of hPBGD== | ||
===Acute Intermittent Porphyria=== | ===Acute Intermittent Porphyria=== | ||
==References== | ==References== | ||
<references/> | <references/> | ||
