rise to a wealth of interesting new marine natural products. in the deep-sea bacterium Photo sp. 4 Bryozoa computational studies on the polyketide synthase pathway have The colonial bryozoans (moss animals,lace corals)are well specie Thehigh pressures experienced by deep-sea organisms are pthsofovermThe sccondary metabo bryozoans have been reviewed elsewhere, and although an themcae ry oted from shallow-v th encoding Chordata(ascidians) the cold-a scidians.co bacterium including anticancer agents such as didemnin Bfrom in ther solidum,diazonamide from Diazon amino acid sequences and 3D structure,such as increased s Deep-water asidians.which have stabilization of greater fraction of prolineand been well documented from both the Atlantic and Pacificoceans ihanchedr ues and abiliz ucialcltectnaloag cular chaperones,in on the secondary metabolites of deep-water ascidians have been reported. tbelonging to the collected by trawling flexi- The structures me of the same spo nge lobatamides G1(79).The lobatamides are structurally mMRbompm nprising tetraether lipi such as those found in of sponge. 'soayu s ofqel jo 3unsisuos spia [euolro eep-sea polerated fatty acids in deen ascidian Riterella by dredging at pacteria have also been The de n the I orfolk Ric wa In the absence of photosynthesis. chemosynthesis is the ated sesquiterpenes(1015).which are the first examples of dominant metabolic pathway in the deep furanoterpenes from a marine tunicate."0 mino cituiehanSearienCnaaohcrdp 6 Cnidaria The phylum Cnidaria,comprising of the four classes Hydrozoa tila ch is en iosvnthesi source (after dines and the deep-sea nematode nema sp. ew marine natur lternative electron accentor to oxy en,thereby allowing it to inhabit deeper.anoxic sediments Taken together,the above have been reported on the secondary metabolites produced by 11341Nat.Prod.Rep,.2008,25,1131-1166 This journal isThe Royal Society of Chemistry008 more pressure resistant,61 while dihydrofolate reductase isolated from the bacteria has shown increasing activity with increasing pressures up to 100 MPa.62 Pressure-regulated genes have also been discovered in the deep-sea bacterium Photobacterium sp. (strain SS9), including the genes for the outer membrane protein ompH and the porin-like protein ompL.63,64 Furthermore, computational studies on the polyketide synthase pathway have revealed that high pressure may have a beneficial effect on certain secondary metabolic pathways over others.65 The high pressures experienced by deep-sea organisms are expected to affect the conformational shape of proteins and membranes, and their associated activity and binding processes. A range of thermophilic and psychrophilic enzymes have been isolated from deep-sea microorganisms, including a-glucosidase from the deep-sea bacterium Geobacillus from the Mariana Trench,66 a-amylase and lipase from the actinomycete Nocardiopsis and the bacterium Psychrobacter respectively (both obtained from deep-sea sediment from Prydz Bay, Ant￾arctica67,68) and the genes encoding the cold-adapted chaper￾ones DnaK and DnaJ from the deep-sea psychrotrophic bacterium Pseudoalteromonas sp. SM9913, have also been characterised.69 It has been found that proteins in thermophilic organisms, relative to their mesophilic counterparts, show differences in amino acid sequences and 3D structure, such as increased stabilization of a-helices, a greater fraction of proline and b-branched residues and fewer uncharged polar residues, along with increased protein stabilization through crucial electrostatic interactions and a heightened role for molecular chaperones, in particular the heat shock proteins.48,49,70,71 Conversely, psychro￾philic proteins and enzymes display a reduced number of inter￾actions involved in protein stability such as decreased proline residues and salt bridges, thereby leading to increased flexi￾bility.51,52,72 Other mechanisms of cold-adaptation42 include the presence of antifreeze proteins73,74 increased levels of trimethyl￾amine oxides75,76 and incorporation of exopolysaccharides into microbial cell membranes.74,77 Membranes comprising tetraether lipids such as those found in deep-sea archaea appear more resistant to higher temperatures than bacterial lipids consisting of labile ester linkages. Moreover, deep-sea organisms have been found to modulate their membrane fluidity and stabilization, through elements such as the incorporation of high levels of polyunsaturated fatty acids,48 and the bacterial genes responsible for the biosynthesis of polyunsaturated fatty acids in deep-sea bacteria have also been reported.78 In the absence of photosynthesis, chemosynthesis is the dominant metabolic pathway in the deep sea. The genome sequence of the deep-sea g-protobacterium Idiomarina loihiensis reveals that the organism obtains its energy from catabolism of amino acids rather than sugar fermentation.74 Other deep-sea invertebrates are involved in highly specialized symbiotic associations, such the hydrothermal-vent-inhabiting tube worm Riftia pachyptila, which is entirely dependent on a sulfur￾oxidizing, endosymbiotic bacterium for the de novo biosynthesis of pyrimidines,79 and the deep-sea nematode Stilbonema sp., which relies on nitrate reduction by ectosymbiotic bacteria as an alternative electron acceptor to oxygen, thereby allowing it to inhabit deeper, anoxic sediments.80 Taken together, the above adaptions to deep-sea life and their effect on gene regulation and primary and secondary metabolic pathways are certain to give rise to a wealth of interesting new marine natural products. 4 Bryozoa The colonial bryozoans (moss animals, lace corals) are well represented in the marine environment, with over 5000 species described, ranging from shallow-water species to those living at depths of over 4000 m.81–83 The secondary metabolites of bryozoans have been reviewed elsewhere,84–86 and although shallow-water species have furnished such medicinally important compounds as the anti-cancer agent bryostatin 1 isolated from Bugula neritina, 87–89 there appear to be no reports as yet on the isolation, characterisation or bioactivity of secondary metabo￾lites from deep-sea bryozoans. 5 Chordata (ascidians) Shallow-water ascidians, comprising over 2000 known species, have yielded a diverse array of biologically important metabo￾lites90,91 including anticancer agents such as didemnin B from Trididemnum solidum, diazonamide from Diazona angulata, and the recently approved anticancer drug ectinascidian 743 from Ecteinascidia turbinata. 12,92 Deep-water ascidians, which have been well documented from both the Atlantic and Pacific oceans and up to depths of over 8000 m,93–95 present a potentially rich source of interesting new metabolites. To date, only two reports on the secondary metabolites of deep-water ascidians have been reported. A deep-water tunicate belonging to the genus Aplidium, collected by trawling in the Great Australian Bight, has yielded the novel macrolides lobatamides A–F (1–6).96,97 The structures of aplidites E–G, described earlier from the same sponge specimen,14 were revised and the metabolites renamed as the lobatamides G–I (7–9).13 The lobatamides are structurally related to the salicylihalamides isolated from a Haliclona species of sponge, but differing by the presence of the unique conjugated oxime methyl ether. The lobatamides, which were also obtained from shallow-water collections of Aplidium lobatum (SW Aus￾tralia) and an unidentified Philippine ascidian, exhibited signifi- cant cytotoxicity in the NCI 60 human tumour cell line screen, and are the subject of several recent total syntheses.98,99 The deep-sea ascidian Ritterella rete, collected by dredging at a depth of 300 m on the Norfolk Ridge, New Caledonia, was found to contain six new cytotoxic dendrolasin-type hydroxyl￾ated sesquiterpenes (10–15), which are the first examples of furanoterpenes from a marine tunicate.100 6 Cnidaria The phylum Cnidaria, comprising of the four classes Hydrozoa (hydroids), Anthozoa (anemones, corals, sea pens), Scyphoza (jellyfish), and Cuboza (box jellyfish), are well represented in the deep sea. Cnidarians are the second largest source (after sponges) of new marine natural products reported each year, with a predominance of terpenoid metabolites.101–103 Herein, of the four cnidarian classes, only a small handful of examples have been reported on the secondary metabolites produced by 1134 | Nat. Prod. Rep., 2008, 25, 1131–1166 This journal is ª The Royal Society of Chemistry 2008