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First published online July 25, 2005
Journal of Experimental Biology 208, 2819-2830 (2005)
Published by The Company of Biologists 2005
doi: 10.1242/jeb.01730

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Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses

Paul H. Yancey

Biology Department, Whitman College, Walla Walla, WA 99362, USA

View larger version (42K): [in a new window]   Fig. 1. Patterns of osmolyte distributions in marine animals and mammalian kidneys, shown as estimates of intracellular concentrations. Panels from left to right: (1) sharks and other elasmobranchs are dominated by urea and TMAO (data for Squalus acanthias); (2) shallow-water invertebrates, such as the polychaete worm Glycera, snail Mitrella carinata and clam Saxidomus giganteus, are typically dominated by taurine, betaine and -amino acids (AAs) such as glycine; (3) invertebrates from 2.9 km depth, such as the polychaete worm Glycera and snail Neptunea lyrata, have less taurine and other amino acids and more scyllo-inositol, GPC, and unknowns, while a snail (Depressigyra globulus) from hydrothermal vents at 1.5 km depth has high levels of hypotaurine and thiotaurine; (4) vesicomyid clams (Calyptogena spp.) from sulfide seeps have hypotaurine and thiotaurine and show a depth-related increase in an unsolved serine–phosphoethanolamine solute (Ser-P-Eth-X) and an unknown methylamine; (5) vestimentiferan tubeworms (Riftia pachyptila) from hydrothermal vents at 2.6 km depth have high amounts of hypotaurine and an unknown methylamine, both in vestiment tissue (Vest.) and trophosome (Troph., location of sulfide-oxidizing microbial symbionts), which also has high levels of thiotaurine; (6) mammalian renal cells (inner medulla) have varying levels of sorbitol, myo-inositol, GPC, betaine and taurine (along with urea). Data from Peterson et al. (1992); Yin et al. (2000); Yancey et al. (2002); Fiess et al. (2002); Rosenberg et al. (2003).

View larger version (21K): [in a new window]   Fig. 2. Examples of organic osmolytes in three of the four major categories; the fourth category, urea, is not shown. TMAO, trimethylamine N-oxide; GPC, glycerophosphorylcholine; DMSP, dimethylsulfonoproprionate.

View larger version (39K): [in a new window]   Fig. 3. Old and new examples of counteraction between urea and trimethylamine N-oxide (TMAO). (A) Extent of refolding of denatured great white shark A4-lactate dehydrogenase (LDH) in physiological buffer with no osmolytes (control), 400 mmol l–1 urea, 200 mmol l–1 TMAO or combined urea:TMAO (2:1) (data from Yancey and Somero, 1979). (B) Free energy (G) of unfolding of E. coli tRNAfmet in physiological buffer with no osmolytes (control), 2 mol l–1 urea, 1 mol l–1 TMAO or combined urea:TMAO (2:1) (data from Gluick and Yadav, 2003).

View larger version (21K): [in a new window]   Fig. 4. Trimethylamine N-oxide (TMAO) as a possible pressure counteractant in deep-sea animals (see also Fig. 1 for other deep-sea osmolytes). (A) Contents of TMAO (and urea in rajids, as shown) in muscles as a function of depth in shrimp, rajids (skates) and teleost fishes: gadid (cod) and related macrourids (grenadiers), plus scorpaenids (rockfish) (data from Kelly and Yancey, 1999; Yancey et al., 2004). (B) Effect of 250 mmol l–1 osmolytes on NADH Km of A4-lactate dehydrogenase (LDH) from deep-sea grenadier (Coryphaenoides armatus). Measurements were made at atmospheric pressure (0.1 MPa) and 250 atmos (25 MPa), showing that TMAO counteracts pressure better than other common solutes. *Significant increase compared to 0.1 MPa water control; significant decrease compared to 25 MPa water control (modified from Yancey et al., 2004).

View larger version (26K): [in a new window]   Fig. 5. Model of trimethylamine N-oxide (TMAO), urea and pressure effects on protein folding, based on basic pressure effects (Siebenaller and Somero, 1989), counteracting effects (Yancey et al., 1982) and osmolyte physicochemical studies of Timasheff (1992), Bolen and Baskakov (2000) and Bennion and Daggett (2004). Small spheres represent water molecules. (A) An unfolded protein and/or substrate (S) with hydration layers at a higher density than that of bulk water. (B) Thus, upon folding and/or ligand binding, there is a net expansion (+V) as water molecules are released into bulk water during folding. If this is the case, hydrostatic pressure will inhibit folding and/or binding (A). (C) Addition of urea (U) enhances unfolding since that maximizes favorable binding interactions. In B, TMAO (T) is surrounded by its own structured water layer, which disfavors exposure of the protein's peptide backbone and of the substrate to bulk water. TMAO thus favors folding and binding, reducing the total order (higher in A and C).

View larger version (38K): [in a new window]   Fig. 6. Specific ion conductance (Gm) of the wild-type and F508 mutant cystic fibrosis transmembrane-conductance regulator (CFTR) in forskolin-stimulated transfected mouse fibroblast cells. The untreated mutant cells have very low conductance compared with the wild type, while cells exposed to 300 mmol l–1 of the indicated osmolytes had conductance rates as great or greater than the wild type (modified from Howard et al., 2003). *Significant difference compared to wild type.