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[[Image:Selected Cys.png|style="width:300px;height:300px;"'|Lipocalin Prostaglandin D2 Synthase with Cys Residues (65, 89, & 186 labelled) necessary for ligand bonding & maintaining structure]] | [[Image:Selected Cys.png|style="width:300px;height:300px;"'|Lipocalin Prostaglandin D2 Synthase with Cys Residues (65, 89, & 186 labelled) necessary for ligand bonding & maintaining structure]] | ||
<img src="Selected Cys.png" alt="Mountain View" style="width:304px;height:228px;"> | |||
== References == | == References == | ||
<references/> | <references/> | ||
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Lipocalin-Type Prostaglandin D Synthase (L-PGDS)Lipocalin-Type Prostaglandin D Synthase (L-PGDS)
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Lipocalin-type Prostaglandin D Synthase (L-PGDS; originally known as Beta Trace) is the second most abundant protein in the human cerebrospinal fluid. It is involved in the transport of hydrophobic molecules as well as its namesake in the production of prostaglandin D2: an unsaturated fatty acid that is involved in maintaining homeostasis, regulating sleep, aiding in inflammatory responses, and other neurological functions. Although structurally and biochemically different from hematopoietic-PGD synthase, they both take part in the arachidonate cyclooxygenase pathway to make PGD from PGH2. The smaller of the two PGD synthases, L-PGDS contains a beta-barrel structure and was initially found in the brain. It was later discovered in the tissues of the heart, kidneys, and lungs as well as a number of other body fluids. Inhibiting this enzyme results in the deterioration and lack of function of major organs and metabolic processes and has been found to be linked to some cancers, hair loss, and diabetes. L-PGDS can trigger both pro- and anti-inflammatory responses to the immune system, allowing its levels to be highly regulated. [1][2][3]
FunctionFunction
- Ligand Binding
- Retinoids, bilirubin, biliverdin, and thyroid hormone with high affinities (Km = 30-80 nM) often bind to L-PGDS for transport. Transport of these molecules via L-PGDS occurs within the cerebral spinal fluid to the necessary location of the central nervous system. Retinoids have been found to bind on a separate site than the prostagladin active site (Cys65 residue not necessary for retinoid binding). These ligands can act as a noncompetive inhibitor for PGD2 synthesis and transport. [4][2]
- PGD2 Synthesis and Transport
- Teaming up with sulfurhydryl compounds, L-PGDS synthesizes prostaglandin D2 from PGH, a necessary but unstable unsaturated fatty acid used in temperature and hormone regulation, responsible for pain and olfactory responses, and sleep modulation. [1] L-PGD synthase also transports this eicosanoid through the extracellular space to its receptors in order to prevent early PGD2 metabolism. [5]
Diseases/MalfunctionsDiseases/Malfunctions
L-PGDS is a highly stable enzyme and often unaffected by thermal denaturation and protease activities. [5] The following may result in response to a lack of L-PGDS or its function:
- inflammation
- deterioration of brain, heart, & liver
- immunodeficiency
- lack of pain response/inability to feel pain
- insomnia & sleep deprivation [5]
- renal damage
- egg allergy
- cerebral spinal fluid leak
- congenital disorder of glycosylation[6]
Structural HighlightsStructural Highlights
L-PGDS shares the antiparallel beta barrel structure that is common within the lipocalin protein family. The active site for the protein is embedded in this beta barrel. The Cys65 in the center of the barrel, unique only to LPGDS, is the essential residue in the binding of the PGD2 for isomerization and other small hydrophobic molecules for transport. L-PGDS has two hydrophobic pockets located on opposite sides to one another used in ligand binding and transport. Cys89 & Cys186 also form a disulfide bridge within lipocalin prostaglandin D synthase that is common in most but not all lipocalins. [5]
<img src="Selected Cys.png" alt="Mountain View" style="width:304px;height:228px;">
ReferencesReferences
- ↑ 1.0 1.1 Joo M, Sadikot RT. PGD synthase and PGD2 in immune resposne. Mediators Inflamm. 2012;2012:503128. doi: 10.1155/2012/503128. Epub 2012 Jun 25. PMID:22791937 doi:http://dx.doi.org/10.1155/2012/503128
- ↑ 2.0 2.1 Beuckmann CT, Aoyagi M, Okazaki I, Hiroike T, Toh H, Hayaishi O, Urade Y. Binding of biliverdin, bilirubin, and thyroid hormones to lipocalin-type prostaglandin D synthase. Biochemistry. 1999 Jun 22;38(25):8006-13. PMID:10387044 doi:http://dx.doi.org/10.1021/bi990261p
- ↑ Perduca, M., Bovi, M., Bertinelli, M., Bertini, E., Destefanis, L., Carrizo, M. E., Capaldi, S. & Monaco, H. L. (2014). High-resolution structures of mutants of residues that affect access to the ligand-binding cavity of human lipocalin-type prostaglandin D synthase. Acta Cryst. D70, 2125-2138.
- ↑ Tanaka T, Urade Y, Kimura H, Eguchi N, Nishikawa A, Hayaishi O. Lipocalin-type prostaglandin D synthase (beta-trace) is a newly recognized type of retinoid transporter. J Biol Chem. 1997 Jun 20;272(25):15789-95. doi: 10.1074/jbc.272.25.15789. PMID:9188476 doi:http://dx.doi.org/10.1074/jbc.272.25.15789
- ↑ 5.0 5.1 5.2 5.3 Urade Y, Eguchi N, Hayaishi O. Lipocalin-Type Prostaglandin D Synthase as an Enzymic Lipocalin. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6621/
- ↑ http://www.genecards.org/cgi-bin/carddisp.pl?gene=PTGDS#snp
- ↑ Flower, D. R. (1996). The lipocalin protein family: structure and function. Biochemical Journal, 318(Pt 1), 1–14.
- ↑ DOI: 10.2210/pdb2czt/pdb