Alpha-1-acid glycoprotein

doi:10.1016/S0167-4838(00)00153-9

Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology

Volume 1482, Issues 1–2, 18 October 2000, Pages 157-171

Biochimica et Biophy...

https://doi.org/10.1016/S0167-4838(00)00153-9 Get rights and content

Abstract

Alpha-1-acid glycoprotein (AGP) or orosomucoid (ORM) is a 41–43-kDa glycoprotein with a pI of 2.8–3.8. The peptide moiety is a single chain of 183 amino acids (human) or 187 amino acids (rat) with two and one disulfide bridges in humans and rats,respectively. The carbohydrate content represents 45% of the molecular weight attached in the form of five to six highly sialylated complex-type-N-linked glycans. AGP is one of the major acute phase proteins in humans, rats, mice and other species. As most acute phase proteins, its serum concentration increases in response to systemic tissue injury, inflammation or infection, and these changes in serum protein concentrations have been correlated with increases in hepatic synthesis. Expression of the AGP gene is controlled by a combination of the major regulatory mediators, i.e. glucocorticoids and a cytokine network involving mainly interleukin-1β (IL-1β), tumour necrosis factor-α (TNFα), interleukin-6 and IL-6 related cytokines. It is now well established that the acute phase response may take place in extra-hepatic cell types, and may be regulated by inflammatory mediators as observed in hepatocytes. The biological function of AGP remains unknown; however,a number of activities of possible physiological significance, such as various immunomodulating effects, have been described. AGP also has the ability to bind and to carry numerous basic and neutral lipophilic drugs from endogenous (steroid hormones) and exogenous origin; one to seven binding sites have been described. AGP can also bind acidic drugs such as phenobarbital. The immunomodulatory as well as the binding activities of AGP have been shown to be mostly dependent on carbohydrate composition. Finally, the use of AGP transgenic animals enabled to address in vivo, functionality of responsive elements and tissue specificity, as well as the effects of drugs that bind to AGP and will be an useful tool to determine the physiological role of AGP.

Introduction

Alpha-1-acid glycoprotein (AGP) or orosomucoid was concomitantly first described in 1950 by Karl Schmid [1], [2] and Richard J. Winzler and colleagues [3], and turned out to be a very unusual protein: a very low pI of 2.8–3.8 and a very high carbohydrate content of 45%. For about 30 years, AGP was considered to be the protein with the highest carbohydrate content. In 1980, galactoglycoprotein that had a carbohydrate moiety of 76% was described [4], [5]. Although numerous articles were devoted to AGP since 1950, its exact biological function remains obscure. However, numerous activities of potential physiological significance have been described, such as various immunomodulating effects, the ability to bind basic drugs and many other molecules like steroid hormones, the latter leading to the suggestion that AGP might be a member of the lipocalin family. In addition, AGP serum concentrations that remain stable in physiological conditions (about 1 g/l in humans and 0.2 g/l in rats) increase several-fold during acute-phase reactions and AGP is considered as a major member of the positive acute phase protein family.

In this chapter, we will focus on: (1) the AGP protein and corresponding gene structures; (2) the regulation of its hepatic as well as extra-hepatic expression; and (3) the biological functions of AGP.

Section snippets

AGP structure

Human AGP is a glycoprotein of 41–43 kDa in molecular weight, which consists approximately of 45% carbohydrate [6] attached in the form of five complex-type N-linked glycans [7]. AGP has been crystallised as the Pb²⁺ salt in the form of hexagonal bipyramids [2]. An unusually high solubility (in water and in many polar organic solvents) is another notable characteristic of AGP. Different forms of AGP can be distinguished in serum depending on the type of glycosylation and multiple amino acid

AGP hepatic expression and its regulation

Alpha-1 acid glycoprotein is one of the plasma proteins synthesised by the liver and is mainly secreted by hepatocytes, although extra-hepatic AGP gene expression has also been reported and will be discussed in the next section. Hepatic production of these proteins, termed the acute phase proteins (APPs), is increased following the response to various stressful stimuli: physical trauma, such as surgery or wounding, bacterial infection, or unspecific inflammatory stimuli, such as subcutaneous

AGP extra-hepatic expression and its regulation

Extra-hepatic production of AGP and of other acute phase proteins has been described for the last 40 years. However, the regulation of extra-hepatic AGP gene expression has only been examined recently, and the hypothesis that an acute phase response may take place in extra-hepatic cell types and may be regulated by inflammatory mediators as observed in hepatocytes is now well admitted (Table 1).

The first evidence of the presence of AGP as well as other serum glycoproteins in extra-hepatic

Immunomodulatory properties

AGP is considered as a natural anti-inflammatory and immunomodulatory agent notably with respect to its anti-neutrophil and anti-complement activity [111]. Indeed, AGP has been shown to act in vitro and in vivo as an immunomodulating molecule. In vitro, AGP inhibits polymorphonuclear neutrophil activation [112], increases the secretion of an IL-1 inhibitor by murine macrophages, most probably the IL-1 receptor antagonist [113], [114], and modulates LPS-induced cytokine secretion by

Acknowledgments

We are grateful to Pr. G. Durand for valuable criticism.

References (151)

H.E. Weimer et al.
J. Biol. Chem.
(1950)
K. Schmid et al.
J. Biol. Chem.
(1980)
K. Schmid et al.
Biochim. Biophys. Acta
(1977)
H. Yoshima et al.
J. Biol. Chem.
(1981)
D. Biou et al.
Clin. Chim. Acta
(1991)
D. Biou et al.
Clin. Chim. Acta
(1989)
N. Serbource-GoguelSeta et al.
J. Hepatol.
(1986)
J.M. Wieruszeski et al.
FEBS Lett.
(1988)
G.A. Ricca et al.
J. Biol. Clin.
(1981)
G.A. Ricca et al.
J. Biol. Chem.
(1981)

R. Cooper et al.

J. Biol. Chem.

(1986)

K.C. Carter et al.

Biochim. Biophys. Acta

(1991)

B.K. Ray et al.

Biochem. Biophys. Res. Commun.

(1991)

B.K. Ray et al.

Biophys. Res. Commun.

(1992)

H. Baumann et al.

Immunol. Today

(1994)

A.B. Kulkarni et al.

J. Biol. Chem.

(1985)

T. Alam et al.

J. Biol. Chem.

(1993)

A. Koj et al.

Int. J. Biochem. Cell. Biol.

(1995)

H. Baumann et al.

J. Biol. Chem.

(1983)

H. Baumann et al.

J. Biol. Chem.

(1992)

H. Baumann et al.

J. Biol. Chem.

(1993)

T. Ratajczak et al.

J. Biol. Chem.

(1992)

K.C. Carter et al.

J. Biol. Chem.

(1989)

M. Yiangou et al.

Biochim. Biophys. Acta

(1993)

M. Adesnik et al.

J. Biol. Chem.

(1981)

T. Fournier et al.

Biochem. Pharmacol.

(1994)

T. Fournier et al.

J. Biol. Chem.

(1994)

J.S. He et al.

J. Biol. Chem.

(1991)

N. Mejdoubi et al.

Biochem. Biophys. Res. Commun.

(1999)

J.B. Yoon et al.

J. Biol. Chem.

(1990)

S.S. Twining et al.

Clin. Chim. Acta

(1977)

T. Thomas et al.

J. Biol. Chem.

(1989)

E.P. Molmenti et al.

J. Biol. Chem.

(1993)

K. Schmid

J. Am. Chem. Soc.

(1950)

K. Schmid

J. Am. Chem. Soc.

(1953)

H.G. Schwick, H. Haupt, in: F.W. Putnam (Ed.), The Plasma Proteins, Vol. IV, 2nd edn., Academic Press, New York, 1984,...

K. Schmid, in: F.W. Putman (Ed.): The Plasma Proteins, Academic Press, New York, 1975, pp....

K. Schmid et al.

Biochemistry

(1973)

H. Toh et al.

Nature

(1985)

W. Van Dijk

Glycoconj. J.

(1995)

M. Jezeguel et al.

Clin. Chim. Acta

(1988)

G. Ashwell et al.

Annu. Rev. Biochem.

(1982)

M. Yoshima et al.

J. Biol. Chem.

(1981)

A. Drechou et al.

Eur. J. Cell. Biol.

(1989)

S.C. Lee et al.

DNA

(1989)

L. Dente et al.

EMBO J.

(1987)

L. Dente et al.

Genes Dev.

(1988)

Y.C. Liao et al.

Mol. Cell Biol.

(1985)

C.J. Chang et al.

DNA Cell Biol.

(1992)

J. Prowse et al.

J. Biol. Chem.

(1990)

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ReviewAlpha-1-acid glycoprotein

Abstract

Introduction

Section snippets

AGP structure

AGP hepatic expression and its regulation

AGP extra-hepatic expression and its regulation

Immunomodulatory properties

Acknowledgments

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Clin. Chim. Acta

Clin. Chim. Acta

J. Hepatol.

FEBS Lett.

J. Biol. Clin.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Biophys. Res. Commun.

Immunol. Today

J. Biol. Chem.

J. Biol. Chem.

Int. J. Biochem. Cell. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Clin. Chim. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Biochemistry

Nature

Glycoconj. J.

Clin. Chim. Acta

Annu. Rev. Biochem.

J. Biol. Chem.

Eur. J. Cell. Biol.

DNA

EMBO J.

Genes Dev.

Mol. Cell Biol.

DNA Cell Biol.

J. Biol. Chem.

Review
Alpha-1-acid glycoprotein