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Dr Andrew Morby  -  PhD


Transition Metals and Microbes

Transition-metal ions present an interesting chemical paradox to living cells.  Whilst these cations have significant toxicity and can act as potent disrupters of biological systems, a wide spectrum, however, are also essential (micro-) nutrients, since they play important roles in many biochemical processes, either by facilitating redox reactions or by stabilising chemical / protein structure. An improved understanding of metal-ion metabolism is crucial given the fundamental importance of metal-ions chemistry in the cell (e.g. the generation of reactive oxygen species, electron transport, ribosomal function, transcription, replication).  Increasingly, many metabolic disorders (e.g  diabetes, hereditary haemochromatosis, Menkes’ disease and Wilson’s disease) and neurodegenerative diseases (e.g. Alzheimers, Creutzfeld-Jacob), are thought to result from aberrant metal-ion metabolism.

A fundamental aspect of metal-ion metabolism that remains relatively uncharacterised is the context and number of metal-ions within cells.  To date there is little data detailing the proteins/nucleic acids/metabolites that bind metal-ions within the cell and how their association with cellular components impacts their biological availability and activity.

Cyclic di-Guanosine Monophosphate (c-di-GMP)

Cyclic-di guanosine monophosphate (c-di-GMP) has been implicated in the regulation of exo-polysaccharide production and the the switch between sessility and motility in bacteria. The current dogma is that the production of this signalling molecule is controlled by the GGDEF domain protein, e.g. PleD (Hecht & Newton, 1995; Aldridge et al., 2003). 

The GGDEF domain, is both widespread and numerous in prokaryotes and has been shown to have a diguanylate cyclase  (DGC) activity, with a role in the production of c-di-GMP from GTP (Tal et al 1998).  The majority of bacterial genomes harbour multiple genes that appear to encode GGDEF-domain proteins in addition to the “opposing” EAL domain proteins that have been shown to degrade c-di-GMP (phosphodiesterase (PDE) indeed Vibrio vulnificus has up to 59 such examples. What was first identified as an allosteric regulator of cellulose synthesis is now thought to represent a key second messenger in an elaborate and universal bacterial post-translational regulation system (Reviewed in Jenal 2004, D’Argenio and Miller, 2004;Romling et al., 2005).

The opposing cycles of c-di-GMP generation and degradation form the basis of a multi-input signal transduction system that has a global effect on bacterial behaviour, fitness and adaptation to the enviroment.

We are seeking to understand the action of this network in E.coli by the use of a range of molecular and genomic approaches.  Outstanding questions include , what are the input signals to these catalytic centres?, what are the outputs (e,g, cellulose synthesis)?, what roles do the many GGDEF and EAL proteins play in the cell?

Grants Awarded Since 1996

BBSRC
College Res Comm
Wellcome

Collaborations

In all of the above projects, an extensive range of collaborations is enjoyed with scientists in both industrial and academic laboratories including:

University of Birmingham

Professor N.L. Brown
Dr. J.L. Hobman
Dr. J. Wilson

Molecular Light Technologies

Dr. Stuart Woodhead
Dr. Ian Weeks
Dr. Jennifer Cryer

Affiliated Staff

Dr. Sam Marshall Wellcome (RA1A)
Mr Steve Megit BBSRC (RA1B)
Saira Khan PhD
Emma James PhD
Michael Bertels PhD
Michael Allen PhD