Results: 3

1.
Figure 13.3

Figure 13.3. From: Ghrelin O-Acyltransferase Assays and Inhibition.

GHS-R1a assay in stably transfected HEK-293T-GHS-R1a cells. (A) Typical dose–response traces for acyl ghrelin, with concentrations on half-log scale from 1 μM to 100 pM, with buffer-only control. (B) Agonism for acyl ghrelin, GO-Tat (Fig. 13.2, Compound 9), and the bisubstrate compound Ghrelin28-Oct-CoA (Fig. 13.2, Compound 11). EC50 values are reported in Table 13.1.

Martin S. Taylor, et al. Methods Enzymol. 2012;514:205-228.
2.
Figure 13.1

Figure 13.1. From: Ghrelin O-Acyltransferase Assays and Inhibition.

Ghrelin biosynthetic pathway. Ghrelin is synthesized as a 117-amino acid precursor, preproghrelin, containing a signal peptide, the 28-amino acid ghrelin sequence, and a 66-amino acid C-terminal peptide. The signal peptide is cotranslationally cleaved, releasing the 94-amino acid proghrelin into the lumen of the endoplasmic reticulum (ER). Attachment of the octanoate group to Ser3 of proghrelin occurs in the ER and is catalyzed by GOAT. In secretory granules, prohormone convertase 1/3 (PC1/3) then cleaves at the C-terminus of acyl proghrelin to give the mature acyl ghrelin.

Martin S. Taylor, et al. Methods Enzymol. 2012;514:205-228.
3.
Figure 13.2

Figure 13.2. From: Ghrelin O-Acyltransferase Assays and Inhibition.

GOAT inhibitors. (A) Chemical structures of ghrelin and GOAT inhibitors. 1: Des-acyl ghrelin. 2: Acyl ghrelin. 3: Amide-linked octanoyl ghrelin. 4: Amide-linked 5-mer octanoyl ghrelin with C-terminus amidated. 5: Inhibitors discovered by Garner and Janda (2011). 6: GO-CoA-Tat. 7,8: Bisubstrate compounds with five and three amino acids of ghrelin. 9: GO-Tat: an octanoyl-amide Tat-tagged product analog. 10: Bisubstrate inhibitor with two-carbon acyl group. 11: Ghrelin28-Oct-CoA, a bisubstrate compound. (B) Mechanism-based design strategy of GO-CoA-Tat. The lipid–enzyme interaction is not shown but may be important. Also, the form of ghrelin acylated by GOAT is likely proghrelin; the smaller version is shown for clarity.

Martin S. Taylor, et al. Methods Enzymol. 2012;514:205-228.

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