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Feature: Searching the seven seas

Summer 2009

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Pharmaceutical and agrochemical development could soon benefit from cross-cutting research, funded by BBSRC and the Technology Strategy Board, to discover novel enzymes from marine microbes.

From the ice-covered polar regions of the Arctic and Antarctic to the boiling hydrothermal vents in deep ocean trenches, marine microbes are a vast, diverse and untapped resource.

Microorganisms account for more than 95% of ocean biomass. They feed whole ecosystems, consume waste, and act as the living lungs for our planet. And yet we know relatively little about them. What is certain though, is that they represent a hidden treasure trove of biomolecules, with a wide range of potential applications.

Now, for the first time, academic and industry-based researchers in the fields of marine biotechnology and biocatalysis have come together – combining expertise in powerful screening and selection technologies with high-yielding, scalable and economic enzyme production systems – in the quest for industrially useful novel enzyme catalysts.

New approach to enzyme discovery

Current enzyme identification approaches, such as database mining and sequence alignments, although successful in identifying enzymes, give no guarantee of enzyme activity. But BBSRC-funded researchers at Heriot-Watt University and Plymouth Marine Laboratory (PML) are taking a different approach, which is allowing them to target discovery towards activities of interest and, importantly, is vastly high-throughput.

Working closely with Edinburgh-based company Ingenza, PML scientists are undertaking a programme of enzyme characterisation and gene cloning to identify marine organisms which contain activities of interest. Their efforts are focussed on finding new industrially relevant enzymes for the preparation of pure ‘chiral’ molecules.

"Imagine an enzyme as having a glove-like cavity that binds a substrate," explains PML’s Dr Sohail Ali. "If this glove is right-handed, then one isomer will fit inside and be bound, whereas the other isomer will have a poor fit and is unlikely to bind". In parallel, Ingenza is working with Scottish drug discovery company Aquapharm to screen their diverse collection of over 4,000 marine microorganisms for potential biocatalysts, offering Aquapharm a new route to exploit their collection.

Optimising production

Related work by Professor Mark Keane and colleagues at Heriot-Watt University is looking to establish an explicit link between enzyme structural characteristics and their specificity. "Our approach, which considers controlled enzyme induction/purification and enzyme identification coupled with activity response measurements, is bringing us closer to the identification of industrially relevant amine oxidases," explains Prof. Keane. Such enzymes could be key to a cheaper, more efficient and sustainable process in the production of valuable synthetic target chemicals by both the pharmaceutical and agrochemical industries.

What’s more, the work is not just limited to a commercial outcome. Already, studies at Heriot-Watt University of some of the enzymes of interest are yielding insights into gene and enzyme regulation.

Opening up opportunities in bioprocessing

The enzymes discovered as part of this research are feeding into a patented platform bioprocess, developed by Ingenza, for the purification of chiral biomolecules.

Ingenza’s ‘deracemisation’ process could reduce waste and costs compared to traditional methods used to purify mixtures of chiral compounds, such as solvent partitioning and chromatography. Unlike these methods, which remove the unwanted isomer, deracemisation actually converts the unwanted isomer into the other and therefore increases theoretical product yields from 50% to 100%.

Ingenza’s Dr Robert Speight, says, "The discovery of new enzymes with novel substrate specificities will open up our technology to a number of new markets.

"Once potential enzymes are identified they can be rapidly integrated into our platform manufacturing process leading to new products in increasingly shortened timescales".

"This project has provided an opportunity to exploit our expertise in marine microbiology in new ways, something which would not have been possible without the funding provided by BBSRC," says Dr Ali.

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