Johnny Silva Cancer Research

Octanoylation of Ghrelin

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Collectively, the chemistry-driven conceptualisation of the ghrelin system compellingly fuses the chemistry and biology of bioactive ghrelin into a very special interdependence. The control of regulation of the octanoylating enzyme complex by a potential array of specific metabolic, nutritional and hormonal factors will require elucidating.

Octanoylation of the 28 amino acid ghrelin peptide requires the extraordinary specificity of performing three major precise chemical steps presumably by a specialised enzyme complex that has yet to be characterised or identified. The three steps include addition of only the octanoic car-boxylic or fatty acid and presumably not any other carboxylic or fatty acid to the ghrelin pep-tide, specific addition of the octanoic carboxylic acid to only the ghrelin peptide and not any other peptide hormone, and specifically covalently linking the octanoic carboxylic acid to the hydroxyl group of the side chain of only the Ser3 but not Ser2 of ghrelin via an ester bond. Furthermore, the octanoylating enzyme complex must be distributed at key anatomical sites where the ghrelin peptide is synthesised, likely at intracellular locations and perhaps as a functional complex within vesicles. Because of the envisioned multiple components and requirements of the enzyme complex, octanoylation of the desoctanoyl ghrelin peptide seems unlikely to occur in plasma.

Whether the relatively high concentration of des-octanoylated ghrelin in peripheral plasma originating from the stomach and delivered to the peripheral tissues provides a substrate for the presumed octanoyl enzyme complex in tissues is an important unknown. If this seemingly special enzyme complex function occurs only intracellu-larly, desoctanoyl ghrelin from plasma would be unlikely to be the substrate for the enzyme complex because of the difficulty of delivering it to a specific enzyme octanoylation site within the cell and in an appropriate amount.

In principle, it is necessary to consider a possible biological role for the desoctanoyl ghrelin, the full-length ghrelin peptide without an octanoyl modification. It is secreted from the stomach directly into the peripheral circulation where it is present in higher concentrations than octanoylat-ed ghrelin. Molecular evidence further supports that the desoctanoylated ghrelin peptide is syn-thesised in many tissues of the body, but whether this ghrelin peptide becomes octanoylated is unknown. Although gene expression data indicated that only low concentrations of desoctanoylat-ed ghrelin are synthesised in peripheral tissue, this may dramatically change in select tissues or organs as a function of metabolism, nutrition and/or hormonal secretion.

The first possible biological in vivo action of desoctanoylated ghrelin was recently reported by Thompson et al. [13]. In this novel study, bone marrow fat was increased after the direct continuous infusion of desoctanoyl ghrelin into the tibial marrow cavity of rats for 7 days. However, since infusion of octanoylated ghrelin produced this same effect, the provocative possibility is raised of whether the infused desoctanoylated ghrelin became octanoylated. The studies of Choi et al. demonstrate that ghrelin increases the genesis of rat adipocytes in vitro via the type 1a GHS receptor [14]. More important is that these studies may result in many new conceptual thoughts, strategies and experimental approaches. Because it is known that desoctanoylated ghrelin is not active on the GHS type 1a receptor, while several studies indicate the action of desoctanoyl ghrelin occurs in vitro [15, 16], it will be necessary to re-evaluate approaches to disentangle des- from octanoylated ghrelin actions.

At present, the role and action of ghrelin are frequently indirectly surmised from peripheral plasma immunoactivity levels of 'ghrelin' obtained by various RIAs, each of which have inherent limitations or are incompletely validated for specifically measuring the concentration of the intact bioactive ghrelin molecule. It has been reported by Nagaya et al. that the half-life of ghre-lin after intravenous administration is about 10 minutes. Plasma desoctanoylated ghrelin levels are variable, about five-fold or more greater than plasma octanoylated ghrelin levels. These levels likely vary under pathophysiological conditions or even during normal metabolic, nutritional and hormonal states. In addition to the limitation of this methodology, it is necessary to consider the list of factors in Table 6, which may directly and/or indirectly modulate the level of desoctanoyl ghrelin in peripheral plasma and/or the sensitivity of the ghrelin/GHRP action on GH secretion and food intake. The analysis of the effects of these factors will be focal to the interpretation of the physiological and pathophysio-logical roles of ghrelin.

To date, only octanoylated ghrelin 1-27 has been identified in peripheral human plasma and the stomach by Hosoda et al. [17]. It originates from octanoylated ghrelin 1-28 by cleavage of the Pro27-Arg28 C-terminal bond and has the same

high in vitro and in vivo activity as ghrelin 1-28. Other relevant findings in humans consist of n-decanoylated ghrelin in the stomach and plasma and preliminary evidence that immunoreactive ghrelin in peripheral plasma rapidly decreases to 35% of normal control levels following total gas-trectomy. Because ghrelin levels in plasma are not lower after total gastrectomy, the anatomical origin may be the intestinal tract, where immunore-active ghrelin has been identified. However, the chemical point arises in regard to what degree the full-length ghrelin peptide is present, as well as the octanoylation status in the intestine, plasma and peripheral tissues.