The World's Least Hospitable Environments Are Treasure Troves
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Natural products Extreme potential LIBRARY PHOTO LARSEN/SCIENCE CALVIN The world’s least hospitable environments are treasure troves for synthetic organic chemists and drug developers, reports Bea Perks In 1995, a flock of 300 snow geese unravel the structures of previously migrating across the US state of In short unknown molecules produced by Montana landed on a lake near the Temperature, pressure, these life forms. former mining town of Butte and toxicity and salinity died. Berkeley Pit lake marked the extremes can sustain Life from the jaws of death site of an abandoned open-pit copper unusual organisms The full potential of those molecules mine that had shut down 13 years Extremophile enzymes remains unknown, but there is plenty earlier. Tests on the birds revealed can be more suitable of evidence to suggest they will be exposure to high concentrations of for use in biotechnology significant. For example berkelic copper, cadmium and arsenic. than those from regular acid, isolated from a species of fungus The appeal of the lake – 115 billion species, and their unusual living in the Berkeley Pit lake, has litres of acidic (pH2) metal-laden metabolites are a source been shown to have selective activity water – is not immediately obvious. of potential new drugs against ovarian cancer. But living in that toxic pool are Growing extremophiles The race is on – there is clearly a organisms that could help treat a in the lab is difficult and need to clean up a lake which will kill spectrum of illnesses, from ovarian expensive, so synthesis any passing wildlife. But, perversely, cancer to Alzheimer’s disease. is often required to fully the lake may be harbouring life- Berkeley Pit lake is clearly an evaluate new compounds saving agents for mankind. extreme environment. The idea And it’s a race on several levels. that organisms could thrive in such While the Berkeley Pit lake is a environments wasn’t fully recognised dangerous manmade lake in serious until the 1980s and 1990s. The term need of remediation, there are ‘extremophile’ was first proposed naturally extreme environments in the 1970s by Robert MacElroy, a that require protection in their biochemist working at Nasa’s Ames natural state (see ‘Protecting Research Center in Moffat Field, natural extremes’, p51). One way or US. MacElroy predicted that the another, extremophiles are under inhospitable environment on Mars threat. There is a growing need to could be one day be colonised by devise ways of synthesising the Earth-based life. unusual, but potentially very useful, Biologists have been secondary metabolites produced by busy discovering ever more these organisms. extraordinary organisms inhabiting Among the best studied molecules a range of extreme environments on produced by extremophiles are Earth (see ‘Extreme extremophiles’, enzymes, sometimes referred to p50), prompting chemists to as extremozymes. The enzymes 48 | Chemistry World | June 2011 www.chemistryworld.org The acidic and metal- produced by organisms that inhabit laden waters of Berkeley extreme environments are, not Pit lake in Montana, US, surprisingly, quite unlike the enzymes may seem inhospitable, you will find in a standard textbook but they are home to (see Chemistry World, September bacteria and fungi that 2005, p51). They catalyse reactions produce unique molecules far outside the long-established like berkelic acid temperature, pH and pressure norms, suiting them to a range of biotechnological applications, particularly in the oil industry. More recently, the natural products produced by extremophiles have been attracting attention. These are usually secondary metabolites – molecules that are not directly required to keep the organism alive, but perform some kind of helpful function, such as defence mechanisms and colourings. Hot and cold Several secondary metabolites isolated from thermophilic sources Psychrophilin D (organisms that thrive in the was isolated from a heat) have been shown to have cold-loving fungus in antibacterial activity. For example, Greenland one species of the thermophilic www.chemistryworld.org Chemistry World | June 2011 | 49 Natural products off southern Japan; to a group of ‘It’s a really toxic potential antifoulants capable of environment, fending off barnacle attachment, produced by the bacteria there are unique Streptomyces fungicidicus discovered microbes 5000m deep in the Pacific. and they’re Sturdy old salts producing some The halophiles, organisms that thrive in high salt conditions, counter the really unusual osmotic stress of their surroundings metabolites’ either by accumulating or maintaining concentrations of osmolytes such as KCl close to that of their surroundings. Relatively little is known about the secondary metabolites produced by these organisms, and rather than (+)-Formylanserinone B offering cures for intractable human was isolated from fungi diseases, some of them seem more living 1335m below sea likely to make us ill. A halophilic level, but shows promise Gram-negative bacteria, Vibrio for treating leukaemia parahaemolyticus, was first isolated in 1950 as the cause of seafood poisoning. fungus Streptomyces thermoviolaceus barophiles; organisms that thrive Even less is known about secondary was shown to be a source not only under high pressure). These metabolites produced by organisms of a previously isolated antibiotic organisms normally have to be that thrive at high pH, the alkaliphiles. molecule called granaticin, but also able to withstand extreme cold as The enzymes from these organisms a source of a previously unknown well as high pressure, except for have attracted more attention though, biosynthetic precursor of that the few that live near hot vents. particularly for their use in biological antibiotic called dihydrogranaticin. Secondary metabolite production detergents. Among the secondary metabolites by piezophiles is particularly isolated from psychrophilic sources well studied. A mixture of two From lake to lab (organisms that thrive in the cold), Penicillium corylophilum strains The secondary metabolites produced three cyclic peptides – mixirins A, collected 1335m below sea level by organisms that thrive at low B and C – collected from a Bacillus produced five previously unknown pH, the acidophiles, are a different strain living in the Arctic, were shown compounds. Among these was matter, taking us back to the Berkeley to inhibit the growth of human colon (+)-formylanserinone B, which was Pit lake. Over 40 different bacteria, cancer cells. A species of cold-loving shown to selectively inhibit growth fungi, algae and protozoans, have fungus, Penicillium algidum – which in mouse leukaemia cells. been discovered in this one polluted, was found under a redcurrant bush in Apart from compounds with manmade lake. Despite the ecological Greenland – produces the previously antitumour activity, secondary disaster that the lake represents, unknown compound psychrophilin D, metabolites produced by over 20 previously unknown natural which shows some activity against a piezophiles have been linked to products have been isolated from its mouse leukaemia cell line. a range of applications: from a resident microbe population. previously unknown violet pigment Living in this toxic soup are life Deep, deep down isolated from a species of bacteria forms that researchers predict could Down at the bottom of the (Shewanella violacea), living help treat migraine, high blood ocean are the piezophiles (or 5110m down in an ocean trench pressure, ovarian cancer and lung cancer. One team is beginning to investigate the possibility that there Extreme extremophiles might also be compounds to help Extremophiles turn up in Arctic sea bed – arriving by treat neurological disorders like surprising places. We now some kind of passive transport Alzheimer’s disease. expect to find extraordinary mechanism. He is now figuring ‘It’s a really toxic environment, organisms on the sea floor, out why they are there, and there are some pretty unique in hydrothermal vents, or in what this might tell us about, microorganisms and they’re geysers and hot pools, but for example, the presence of oil producing some really unusual researchers were surprised reserves deep below the sea bed. secondary metabolites,’ says recently to find heat-loving And when they’re not Margaret Brimble, professor of thermophiles in the Arctic. Casey turning up in the ‘wrong’ place, organic and medicinal chemistry at Hubert, a geomicrobiologist at extremophiles can turn up the University of Auckland in New JOEL E KOSTKA E JOEL the University of Newcastle, in just odd places. A couple Zealand. ‘We’re looking at making UK, found thermophiles lying Casey Hubert has found heat- of years ago a Japanese some of those metabolites because dormant in arctic marine loving thermophiles in the Arctic research team discovered a they’ve got some really unusual sediments, where it is 50°C new species of extremophile, structures that we haven’t seen colder than they would need and they sprang back to life. Microbacterium hatanonis, before in the chemical world.’ to grow. Hubert put them in a Importantly, he showed a stable living in hairspray. The bacteria Brimble’s group was the first thermophile-friendly incubator, supply of thermophiles to the grows best at 30°C, pH7. to synthesise berkeleyamide A, a secondary metabolite isolated from 50 | Chemistry World | June 2011 www.chemistryworld.org a Penicillium rubrum Stoll species living in the lake. Considering that the natural source of berkelyamide wouldn’t be available