| Structural highlights
Disease
[ALBU_HUMAN] Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600]. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.[1] [2] [3] [4]
Function
[ALBU_HUMAN] Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.[5]
Publication Abstract from PubMed
BACKGROUND: Serum albumin is a major pharmacokinetic effector of drugs. To gain further insight into albumin binding chemistry, the crystal structures of six oncology agents were determined in complex with human serum albumin at resolutions of 2.8 to 2.0A: camptothecin, 9-amino-camptothecin, etoposide, teniposide, bicalutamide and idarubicin. METHODS: Protein crystal growth and low temperature X-ray crystallography RESULTS: These large, complex drugs are all bound within the subdomain IB binding region which can be described as a hydrophobic groove formed by alpha-helices h7, h8 and h9 covered by the extended polypeptide L1. L1 creates a binding cavity with two access sites, one between loop L1 and alpha-helices h7 and h8 (distal site: IBd) and the other between L1 and alpha-helix h9 (proximal site: IBp). Camptothecin (2.4A) and 9 amino camptothecin (2.0A) are clearly bound as the open lactone form (IBp). Idarubicin (2.8A) binds in a DNA like dimer complex via an intermolecular pi stacking arrangement in IBd. Bicalutamide (2.4A) is bound in a folded intramolecular pi stacking arrangement between two aromatic rings in IBd similar to idarubicin. Teniposide (2.7A) and etoposide (2.7A), despite small chemical differences, are bound in two distinctly different sites at or near IB. Teniposide is internalized via primarily hydrophobic interactions and spans through both openings (IBp-d). Etoposide is bound between the exterior of IB and IIA and exhibits an extensive hydrogen bonding network. CONCLUSIONS: Subdomain IB is a major binding site for complex heterocyclic molecules. GENERAL SIGNIFICANCE: The structures have important implications for drug design and development. This article is part of a Special Issue entitled Serum Albumin.
Structural studies of several clinically important oncology drugs in complex with human serum albumin.,Wang ZM, Ho JX, Ruble JR, Rose J, Ruker F, Ellenburg M, Murphy R, Click J, Soistman E, Wilkerson L, Carter DC Biochim Biophys Acta. 2013 Jul 6. pii: S0304-4165(13)00292-4. doi:, 10.1016/j.bbagen.2013.06.032. PMID:23838380[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sunthornthepvarakul T, Angkeow P, Weiss RE, Hayashi Y, Refetoff S. An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families. Biochem Biophys Res Commun. 1994 Jul 29;202(2):781-7. PMID:8048949
- ↑ Rushbrook JI, Becker E, Schussler GC, Divino CM. Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. J Clin Endocrinol Metab. 1995 Feb;80(2):461-7. PMID:7852505
- ↑ Wada N, Chiba H, Shimizu C, Kijima H, Kubo M, Koike T. A novel missense mutation in codon 218 of the albumin gene in a distinct phenotype of familial dysalbuminemic hyperthyroxinemia in a Japanese kindred. J Clin Endocrinol Metab. 1997 Oct;82(10):3246-50. PMID:9329347
- ↑ Sunthornthepvarakul T, Likitmaskul S, Ngowngarmratana S, Angsusingha K, Kitvitayasak S, Scherberg NH, Refetoff S. Familial dysalbuminemic hypertriiodothyroninemia: a new, dominantly inherited albumin defect. J Clin Endocrinol Metab. 1998 May;83(5):1448-54. PMID:9589637
- ↑ Lu J, Stewart AJ, Sadler PJ, Pinheiro TJ, Blindauer CA. Albumin as a zinc carrier: properties of its high-affinity zinc-binding site. Biochem Soc Trans. 2008 Dec;36(Pt 6):1317-21. doi: 10.1042/BST0361317. PMID:19021548 doi:10.1042/BST0361317
- ↑ Wang ZM, Ho JX, Ruble JR, Rose J, Ruker F, Ellenburg M, Murphy R, Click J, Soistman E, Wilkerson L, Carter DC. Structural studies of several clinically important oncology drugs in complex with human serum albumin. Biochim Biophys Acta. 2013 Jul 6. pii: S0304-4165(13)00292-4. doi:, 10.1016/j.bbagen.2013.06.032. PMID:23838380 doi:10.1016/j.bbagen.2013.06.032
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