Tremendous advances have been achieved in the past 20 years in
our understanding of human serum albumin (HSA). HSA has been a topic
of intense research for scientists from various fields as it is
the most abundant plasma protein and easy to isolate. It is well
known for its extraordinary binding capacity for both endogenous
and exogenous substances, including a wide range of drugs. Binding
of drugs to HSA in the circulatory system is an important factor
which determines the pharmacokinetisc and pharmacological effect
of drugs. Most drugs specifically interact with either two major
drug binding sites, termed as site I and site II, on HSA. Recent
x-ray crystallographic structure of HSA successfully showed that
the location of site I and site II is at subdomain IIA and IIIA,
respectively. However, in view of most functional proteins exhibit
structural dynamics during their functional activities, static structural
information such as x-ray crystallographic data can not completely
reveal the structure-function relationship of the protein. We thus
examine the structural and functional properties of HSA using various
techniques ranging from spectrometry to site-direct mutagenesis.
Protein engineering can be defined as the use of genetic and chemical
techniques to change the structure and function of a protein, thus
producing a novel product with specific, desired, properties. With
the structural and functional data, we proceed to design novel recombinant
albumin with specific pharmaceutical utility of therapeutic applications.
In our research strategy, we have subdivided this main theme into
3 research topics:
1. Topology analysis of the drug binding sites on HSA using
spectrometry, biochemical, molecular
biological and computational modeling techniques.
2. Study of structural and functional changes of HSA under various
disease states.
3. Molecular design and protein engineering of recombinant albumin
with desired functional properties.
Reference(2000〜)
Mera K, Nagai M, Brock JW, Fujiwara Y, Murata T, Maruyama T, Baynes
JW, Otagiri M, Nagai R. Glutaraldehyde is an effective cross-linker
for production of antibodies against advanced glycation end-products.J
Immunol Methods. In press (2008)
Kitamura R, Asanoma H, Nagayama S, Otagiri M. Identification
of human liver cytochrome P450 isoforms involved in autoinduced
metabolism of the anti-angiogenic agent TSU-68 ((Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic
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Katayama N, Nakajou K, Komori H, Uchida K, Yokoe
J, Yasui N, Yamamoto H, Kai T, Sato M, Nakagawa T, Takeya M, Maruyama
T, Otagiri M. Design and evaluation of S-nitrosylated human serum
albumin as a novel anticancer drug. J. Pharmacol. Exp. Ther.,
325, 69-76, (2008)
Inoue K, Nakai Y, Ueda S, Kamigaso S, Ohta KY, Hatakeyama
M, Hayashi Y, Otagiri M, Yuasa H. Functional characterization of
PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal
folate transport system in the rat model. Am. J. Physiol. Gastrointest.
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Anraku, M., Kouno, Y., Kai, T., Tsurusaki, Y., Yamasaki,
K., and Otagiri, M. The role of N-acetyl-methioninate as a new stabilizer
for albumin products. Int. J. Pharm,. 329, 19-24,
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S., Sawa, T., Maruyama, T., Kai, T., and Otagiri, M. Effects of
endogenous ligands on the biological role of human serum albumin
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Ishima Y, Sawa T, Kragh-Hansen U, Miyamoto Y, Matsushita
S, Akaike T, Otagiri M. Related Articles, Links S-Nitrosylation
of human variant albumin Liprizzi (R410C) confers potent antibacterial
and cytoprotective properties. J Pharmacol Exp Ther. 320:969-977
(2007)
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Otagiri M. Related Articles, Links The role of N-acetyl-methioninate
as a new stabilizer for albumin products. Int J Pharm. 329:19-24
(2007)
Mera K, Nagai R, Haraguchi N, Fujiwara Y, Araki T,
Sakata N, Otagiri M. Related Articles, Links Hypochlorous acid generates
N epsilon-(carboxymethyl)lysine from Amadori products. Free Radic
Res. 41:713-718 (2007)
Kragh-Hansen U, Watanabe H, Nakajou K, Iwao Y, Otagiri
M. Related Articles, Links Chain length-dependent binding of fatty
acid anions to human serum albumin studied by site-directed mutagenesis.
J Mol Biol. 363:702-712 (2006)
Matsushita S, Chuang VT, Kanazawa M, Tanase S, Kawai
K, Maruyama T, Suenaga A, Otagiri M. Related Articles, Links Recombinant
human serum albumin dimer has high blood circulation activity and
low vascular permeability in comparison with native human serum
albumin. Pharm Res.23:882-891 (2006)
Chuang VT, Otagiri M. Related Articles, Links Stereoselective
binding of human serum albumin. Chirality.18:159-166
(2006)
Iwao Y, Anraku M, Hiraike M, Kawai K, Nakajou K, Kai
T, Suenaga A, Otagiri M. Related Articles, Links The structural
and pharmacokinetic properties of oxidized human serum albumin,
advanced oxidation protein products (AOPP). Drug Metab Pharmacokinet.
21:140-146 (2006)
Iwao Y, Anraku M, Yamasaki K, Kragh-Hansen U, Kawai
K, Maruyama T, Otagiri M. Related Articles, Links Oxidation of Arg-410
promotes the elimination of human serum albumin. Biochim Biophys
Acta. 1764:743-739 (2006)
Mera K, Anraku M, Kitamura K, Nakajou K, Maruyama
T, Tomita K, Otagiri M. Related Articles, Links Oxidation and carboxy
methyl lysine-modification of albumin: possible involvement in the
progression of oxidative stress in hemodialysis patients. Hypertens
Res. 28:973-980 (2005)
Otagiri M. A molecular functional study on the interactions
of drugs with plasma proteins. Drug Metab Pharmacokinet.
20:309-323 (2005) Review.
Ma SF, Anraku M, Iwao Y, Yamasaki K, Kragh-Hansen U, Yamaotsu N,
Hirono S, Ikeda T, Otagiri M. Hydrolysis of angiotensin II receptor
blocker prodrug olmesartan medoxomil by human serum albumin and
identification of its catalytic active sites. Drug Metab Dispos.
33:1911-1919 (2005).
Ghuman J, Zunszain PA, Petitpas I, Bhattacharya AA, Otagiri M, Curry
S. Structural basis of the drug-binding specificity of human serum
albumin. J Mol Biol. 353:38-52 (2005).
Mera K, Anraku M, Kitamura K, Nakajou K, Maruyama
T, Otagiri M. The structure and function of oxidized albumin in
hemodialysis patients: Its role in elevated oxidative stress via
neutrophil burst. Biochem Biophys Res Commun. 334:1322-1328
(2005).
Nakajou K, Horiuchi S, Sakai M, Hirata K, Tanaka M,
Takeya M, Kai T, Otagiri M. CD36 Is not involved in scavenger receptor-mediated
endocytic uptake of glycolaldehyde- and methylglyoxal-modified proteins
by liver endothelial cells. J. Biochem. 137:607-616
(2005).
Kawasaki CI, Nishi R, Uekihara S, Hayano S, Kragh-Hansen U, Otagiri
M. How tightly can a drug be bound to a protein and still be removable
by charcoal hemoperfusion in overdose cases? Clin Toxicol.
43:95-99 (2005).
Nakajou K, Horiuchi S, Sakai M, Haraguchi N, Tanaka M, Takeya M,
Otagiri M. Renal clearance of glycolaldehyde- and methylglyoxal-modified
proteins in mice is mediated by mesangial cells through a class
A scavenger receptor (SR-A). Diabetologia 48:317-327
(2005).
Takamura N, Maruyama T, Chosa E, Kawai K, Tsutsumi Y, Uryu Y, Yamasaki
K, Deguchi T, Otagiri M. Bucolome, a potent binding inhibitor for
furosemide, alters the pharmacokinetics and diuretic effect of furosemide:
potential for use of bucolome to restore diuretic response in nephrotic
syndrome. Drug Metab. Dispos. 33:596-602 (2005).
Kragh-Hansen U, Saito S, Nishi K, Anraku M, Otagiri M. Effect of
genetic variation on the thermal stability of human serum albumin.
Biochim. Biophys. Acta 1747:81-88 (2005).
Fukuzawa K, Saitoh Y, Akai K, Kogure K, Ueno S, Tokumura A, Otagiri
M, Shibata A. Antioxidant effect of bovine serum albumin on membrane
lipid peroxidation induced by iron chelate and superoxide. Biochim.
Biophys. Acta 1668:145-155 (2005).
Komatsu T, Oguro Y, Teramura Y, Takeoka S, Okai J, Anraku M, Otagiri
M, Tsuchida E. Physicochemical characterization of cross-linked
human serum albumin dimer and its synthetic heme hybrid as an oxygen
carrier. Biochim. Biophys. Acta 1675:21-31 (2004).
Harada D, Anraku M, Fukuda H, Naito S, Harada K, Suenaga A, Otagiri
M. Kinetic studies of covalent binding between N-acetyl-L-cysteine
and human serum albumin through a mixed-disulfide using an N-methylpyridinium
polymer-based column. Drug Metab. Pharmacokinet.19:297-302
(2004).
Yamasaki K, Maruyama T, Takadate A, Suenaga A, Kragh-Hansen U,
Otagiri M. Characterization of site I of human serum albumin using
spectroscopic analyses: Locational relations between regions Ib
and Ic of site I. J Pharm. Sci. 93:3004-3012 (2004).
Anraku M, Tsurusaki Y, Watanabe H, Maruyama T, Kragh-Hansen U,
Otagiri M. Stabilizing mechanisms in commercial albumin preparations:
octanoate and N-acetyl-l-tryptophanate protect human serum albumin
against heat and oxidative stress. Biochim. Biophys. Acta
1702:9-17 (2004).
Matsushita S, Isima Y, Chuang VT, Watanabe H, Tanase S, Maruyama
T, Otagiri M. Functional analysis of recombinant human serum albumin
domains for pharmaceutical applications. Pharm. Res. 21:1926-1934
(2004).
Anraku M, Kitamura K, Shinohara A, Adachi M, Suenaga A, Maruyama
T, Miyanaka K, Miyoshi T, Shiraishi N, Nonoguchi H, Otagiri M, and
Tomita K. Intravenous iron administration induces oxidation of serum
albumin in hemodialysis patients. Kidney Int. 66:
841-848 (2004).
Anraku M, Maruyama T, and Otagiri M. Structural property of albumin
- drug binding sites and dosage plan. J. Med. Tech. 48:521-526
(2004). in Japanese.
Sakurai Y, Ma SF, Watanabe H, Yamaotsu N, Hirono S, Kurono Y, Kragh-Hansen
U, Otagiri M. Esterase-like activity of serum albumin: characterization
of its structural chemistry using p-nitrophenyl esters as substrates.
Pharm. Res. 21: 285-292 (2004).
Nakajou K, Watanabe H, Kragh-Hansen U, Maruyama T, Otagiri M. The
effect of glycation on the structure, function and biological fate
of human serum albumin as revealed by recombinant mutants. Biochim.
Biophys. Acta 1623: 88-97 (2003).
Anraku M, Kragh-Hansen U, Kawai K, Maruyama T, Yamasaki Y, Takakura
Y, Otagiri M. Validation of the chloramine-T induced oxidation of
human serum albumin as a model for oxidative damage in vivo. Pharm.
Res. 20: 684-692 (2003).
Harada D, Naito S, Otagiri M. Kinetic analysis of covalent binding
between N-acetyl-L-cysteine and albumin through the formation of
mixed disulfides in human and rat serum in vitro. Pharm. Res.
19:1648-1654 (2002).
Chuang VT, Otagiri M. How do fatty acids cause allosteric binding
of drugs to human serum albumin? Pharm. Res. 19:1458-1464
(2002).
Kragh-Hansen U, Chuang VT, Otagiri M. Practical aspects of the
ligand-binding and enzymatic properties of human serum albumin.
Biol. Pharm. Bull. 25: 695-704. Review (2002).
Chuang VT, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies
utilizing recombinant human serum albumin. Pharm. Res. 19:
569-577. Review (2002).
Harada D, Naito S, Hiraoka I, Otagiri M. In vivo kinetic analysis
of covalent binding between N-acetyl-L-cysteine and plasma protein
through the formation of mixed disulfide in rats. Pharm. Res.
19:615-620 (2002).
Watanabe H, Yamasaki K, Kragh-Hansen U, Tanase S, Harada K, Suenaga
A, Otagiri M. In vitro and in vivo properties of recombinant human
serum albumin from Pichia pastoris purified by a method of short
processing time. Pharm. Res. 18: 1775-1781 (2002).
Anraku M, Yamasaki K, Maruyama T, Kragh-Hansen U, Otagiri M. Effect
of oxidative stress on the structure and function of human serum
albumin. Pharm. Res. 18:632-639 (2001).
Harada D, Naito S, Kawauchi Y, Ishikawa K, Koshitani O, Hiraoka
I, Otagiri M. Determination of reduced, protein-unbound, and total
concentrations of N-acetyl-L-cysteine and L-cysteine in rat plasma
by postcolumn ligand substitution high-performance liquid chromatography.
Anal. Biochem. 290:251-259 (2001).
Sakai T, Yamasaki K, Sako T, Kragh-Hansen U, Suenaga A, Otagiri
M. Interaction mechanism between indoxyl sulfate, a typical uremic
toxin bound to site II, and ligands bound to site I of human serum
albumin. Pharm. Res. 18: 520-524 (2001).
Watanabe H, Kragh-Hansen U, Tanase S, Nakajou K, Mitarai M, Iwao
Y, Maruyama T, Otagiri M. Conformational stability and warfarin-binding
properties of human serum albumin studied by recombinant mutants.
Biochem. J. 357: 269-274 (2001).
Chuang VT, Otagiri M. Flunitrazepam, a 7-nitro-1,4-benzodiazepine
that is unable to bind to the indole-benzodiazepine site of human
serum albumin. Biochim. Biophys. Acta 1546: 337-345
(2001).
Watanabe H, Tanase S, Nakajou K, Maruyama T, Kragh-Hansen U, Otagiri
M.Role of arg-410 and tyr-411 in human serum albumin for ligand
binding and esterase-like activity. Biochem. J. 349:
813-819 (2001).
Watanebe H, Maruyama T, and Otagiri M. A topological analysis of
the drug binding sites on human serum albumin. Xenobio. Metabol.
and Dispos. 16:264-270 (2001). in Japanese.
Maruyama T and Otagiri M. Application of serum albumin to drug
delivery system. Artificial Blood 9:88-94 (2001).
in Japanese.
Yamasaki K, Rahman MH, Tsutsumi Y, Maruyama T, Ahmed S, Kragh-Hansen
U, Otagiri M. Circular dichroism simulation shows a site-II-to-site-I
displacement of human serum albumin-bound diclofenac by ibuprofen.
AAPS Pharm. Sci. Tech. 14: E12 (2000).
Kawasaki C, Nishi R, Uekihara S, Hayano S, Otagiri M. Charcoal
hemoperfusion in the treatment of phenytoin overdose. Am. J.
Kidney Dis. 35:323-326 (2000).
Kawasaki C and Otagiri M. Effectiveness and its prediction of charcoal
hemoperfusion treatment in drug overdose: A guideline based on the
protein binding percentage of the drug. Xenobio. Metabol. and
Dispos. 15:275-280 (2000). in Japanese.
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