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Orosomucoid ( ORM) or alpha-1-acid glycoprotein ( α1AGp, AGP or AAG) is an acute phase protein found in blood plasma. Orosomucoid was discovered over 70 years ago and belongs to the lipocalin protein family. There are two isoforms of AGP, referred to as AGP1 and AGP2. It is an alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in and has a normal plasma concentration between 0.6–1.2 mg/mL (1–3% plasma protein). Recent research has shown that under certain physiological conditions, brain and adipose tissue can also synthesize this protein. Plasma levels of AGP are affected by pregnancy, burns, certain drugs, and certain diseases, particularly HIV. APG also plays an important role in inflammation and pharmacokinetics, acting as a major transport protein in the blood stream.
The tertiary structure of AGP, determined via X-ray crystallography (PDB ID: 3KQ0), reveals a characteristic beta-barrel fold. Visualization using ChimeraX has provided valuable insights into its conformation and binding pockets.
A study was conducted to compare the different glycosylation sites from patients with acute versus chronic inflammation. The blood serum of patients with acute inflammation showed an increase in bi-antennary and decrease in tri- and tetra-antennary structures, and an increases in alpha1,3-fucosylation, at most glycosylation sites on AGP. In the blood serum of patients with chronic inflammation, higher concentrations of tri-antennary alpha1,3-fucosylation at sites 3 and 4 and tetra-antennary alpha1,3-fucosylation at sites 3, 4 and 5 were detected. In different pathophysiological state (inflammation, rheumatoid arthritis, cancer) alterations of Asn-linked glycans have been reported.
Because AGP possesses a chiral and structurally asymmetric binding pocket, it can interact differently with the enantiomers of various drugs. Studies have shown stereoselective binding for several pharmaceuticals, including proton pump inhibitors and the anti-inflammatory drug Apremilast. In these cases, AGP forms high-affinity complexes with both enantiomers, but with slight differences in stability and interaction strength, indicating that the protein can discriminate between chiral drug molecules.
A notable example is AGP's high binding affinity for 7-hydroxystaurosporine, an anti-cancer drug. AGP limits the drug's effectiveness in humans but not in rats or cattle. Other drugs with strong AGP binding includes but is not limited to the following: Warfarin, Pinometostat, Aripiprazole, Imatinib, Voriconazole, ONO-2160, Brigatinib.
It has been proven that aging causes a small decrease in plasma albumin levels; but tends to not show any change in alpha-1-acid glycoprotein presents in the blood plasma. The effect of any changes on drug protein binding and drug delivery appear to be minimal. (2026). 9780781787635, Lippincott Williams & Wilkins. ISBN 9780781787635 In studies where plasma albumin and alpha-1-acid glycoprotein are monitored for individuals between 20–90 years old, there was a significant decrease in the concentrations of albumin while the concentration of AGP largely remained unchanged
AGP shows a complex interaction with thyroid homeostasis: AGP in low concentrations was observed to stimulate the thyrotropin (TSH) receptor and intracellular accumulation of cyclic AMP. High AGP concentrations, however, inhibited TSH signalling. This specific function of AGP still remains largely unknown and under researched.
Alpha-1-acid glycoprotein has been identified as one of four potentially useful circulating biomarkers for estimating the five-year risk of all-cause mortality (the other three are Serum albumin, very low-density lipoprotein particle size, and citrate). Studies have shown that Alpha 1-acid glycoprotein is an independent predictor death while hospitalized. In a study of 433 patients, from ages 73–92, and all admitted in a rehabilitation department for geriatric medicine the study collected base line alpha 1-acid glycoproteins at baseline and then at discharge or death. This study showed that in the population of discharged patients their baseline alpha 1-acid glycoprotein levels where higher than those who's stay ended with death (1691 +/* 69 mg/l versus 1340 +/- 456 mg/l).
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