The influence of <i>N</i>-acetylneuraminic acid on the properties of human orosomucoid

Friedman, Mark L.; Wermeling, J R; Halsall, H. Brian

doi:10.1042/bj2360149

Cited by 28 publications

(20 citation statements)

References 27 publications

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“…Although there was no detectable change in the trypsin susceptibility or Stern-Volmer constant upon removal of sialic acids from GdA, GdA lost significant anti-proliferative activity. Sialic acid-dependent modulation of activity has been reported previously (27,30). We also observed a reduction of the hydrodynamic volume after removal of sialic acids from GdA.…”

Section: Discussionsupporting

confidence: 68%

“…However, desialylation of GdA decreased its hydrodynamic volume to a value close to that of GdS (Table II). Such a change in hydrodynamic volume upon removal of sialic acids has been reported for another lipocalin, ␣ 1 -acid glycoprotein (27). Reversion of the hydrodynamic volume of desialylated GdA to a value close to that of GdS suggests that the addition of sialic acids exposes an apoptogenic region on the glycodelin backbone that is masked in their absence.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Glycodelin A, Not Glycodelin S, Is Apoptotically Active

Mukhopadhyay¹,

SundarRaj

Alok³

et al. 2004

Journal of Biological Chemistry

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Glycodelin, previously known as PP14 (placental protein-14), is a kernel lipocalin secreted by the glandular epithelium of the endometrium upon progesterone stimulation and by the seminal vesicles. The isoform of the protein present in female reproductive tissue, glycodelin A (GdA), and the male counterpart, glycodelin S (GdS), have identical amino acid sequences, but strikingly different N-linked glycans. It is well documented in literature that GdA is an immunosuppressive protein, and we have shown that this activity is due to its ability to induce apoptosis in activated T cells. The precise role of GdS in seminal plasma is not known. In this study, we report that GdS is not apoptotically active. We observe that the apoptotic activity requires the presence of sialic acid residues on the complex glycans, as in the case of GdA; however, complex glycans of GdS are nonsialylated. We have expressed the wild-type protein in Pichia pastoris, which does not add sialic acid to the secreted proteins, and confirmed our observations that the protein is apoptotically inactive in the non-sialylated form. Our results indicate that differential glycosylation modulates the function of the different glycodelin isoforms.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 86%

Glycodelin A, Not Glycodelin S, Is Apoptotically Active

Mukhopadhyay¹,

SundarRaj

Alok³

et al. 2004

Journal of Biological Chemistry

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“…It is also evident from Table 4 that the AGPphenothiazine system gave higher binding affinities than the asialoAGP-phenothiazine system, particularly for chlorpromazine. A similar large difference in binding constants of chlorpromazine to AGP and asialoAGP was also found by Friedman et al (1986). As the isoelectric points of AGP and asialoAGP were about 2.9 and 4.5, respectively, at pH 7.4, AGP would contain more negative charges than asialoAGP (Kremer et a1 1988).…”

Section: Discussionmentioning

confidence: 53%

Investigation of the Interaction Mode of Phenothiazine Neuroleptics with α1-Acid Glycoprotein

Miyoshi

Sukimoto

Otagiri

1992

Journal of Pharmacy and Pharmacology

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The interaction of phenothiazine neuroleptics with alpha 1-acid glycoprotein (AGP) and desialylated AGP (asialoAGP) has been investigated by fluorescence, circular dichroism spectroscopy and by equilibrium dialysis. The binding parameters of phenothiazines obtained from fluorescence agreed closely with those obtained from circular dichroism and equilibrium dialysis. The binding affinities (nK) to AGP were slightly higher than binding affinities to asialoAGP. Attempts to correlate binding affinities with partition coefficients suggested that hydrophobic forces were mainly involved in the binding of phenothiazine neuroleptics to AGP and asialoAGP. However, electrostatic interaction was also found to be involved as suggested by experimental data obtained from the influence of oleic acid and caesium chloride on the drug binding to the two proteins.

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“…Our results confirm that this protein has the same overall folding as the F1*S variant. The carbohydrate groups on hAGP are thought to have little effect on drug-binding properties and secondary structure (33,34). Our previous findings also demonstrated that the drug-binding capacity of a mutant, C149R, was equivalent to that of the A form purified from serum (35).…”

Section: Discussionmentioning

confidence: 61%

Structural Insights into Differences in Drug-binding Selectivity between Two Forms of Human α1-Acid Glycoprotein Genetic Variants, the A and F1*S Forms

Nishi

Ono

Nakamura³

et al. 2011

Journal of Biological Chemistry

119

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Human ␣ 1 -acid glycoprotein (hAGP) in serum functions as a carrier of basic drugs. In most individuals, hAGP exists as a mixture of two genetic variants, the F1*S and A variants, which bind drugs with different selectivities. We prepared a mutant of the A variant, C149R, and showed that its drug-binding properties were indistinguishable from those of the wild type. In this study, we determined the crystal structures of this mutant hAGP alone and complexed with disopyramide (DSP), amitriptyline (AMT), and the nonspecific drug chlorpromazine (CPZ). The crystal structures revealed that the drug-binding pocket on the A variant is located within an eight-stranded ␤-barrel, similar to that found in the F1*S variant and other lipocalin family proteins. However, the binding region of the A variant is narrower than that of the F1*S variant. In the crystal structures of complexes with DSP and AMT, the two aromatic rings of each drug interact with Phe-49 and Phe-112 at the bottom of the binding pocket. Although the structure of CPZ is similar to those of DSP and AMT, its fused aromatic ring system, which is extended in length by the addition of a chlorine atom, appears to dictate an alternative mode of binding, which explains its nonselective binding to the F1*S and A variant hAGPs. Modeling experiments based on the co-crystal structures suggest that, in complexes of DSP, AMT, or CPZ with the F1*S variant, Phe-114 sterically hinders interactions with DSP and AMT, but not CPZ.

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The influence of N-acetylneuraminic acid on the properties of human orosomucoid

Cited by 28 publications

References 27 publications

Glycodelin A, Not Glycodelin S, Is Apoptotically Active

Glycodelin A, Not Glycodelin S, Is Apoptotically Active

Investigation of the Interaction Mode of Phenothiazine Neuroleptics with α1-Acid Glycoprotein

Structural Insights into Differences in Drug-binding Selectivity between Two Forms of Human α1-Acid Glycoprotein Genetic Variants, the A and F1*S Forms

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