Elucidating and exploiting microbial bioactive product biosynthesis

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20 Φεβ 2013 (πριν από 4 χρόνια και 7 μήνες)

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Principal Supervisor name,
department
, University
:

Prof G. L. Challis, Department of Chemistry,
University of Warwick


Second Supervisor name,
department
, University
:

Dr Lijiang Song, Department of Chemistry,
University of Warwick


Where will
the student
be based
?

Chemical Biology Research Laboratory, Department of Chemistry,
University of Warwick


PhD project title:

Elucidating and exploiting
microbial bioactive
natural product biosynthesis


Project description:

N
atural products have myriad applications,
including: pharmaceuticals, flavours and fragrances, crop
protection
,

and
chemical synthesis. Microorganisms have an extraordinary capacity to produce
natural products with a wide ra
nge of bioactivities. These

include

antibacterial, anticancer,
immunosuppr
essive, insecticidal, herbicidal and fungicidal

activities
.


The biosynthetic pathways for microbial natural products typically involve dozens of enzymes and are
subject to tight temporal regulation. Thus
,

these

pathways represent

remarkable and highly complex
biological systems. Elucidating the molecular mechanisms of
such systems

and exploiting the
knowledge gained for bioengineering of the biosynthetic pathways
,

to boost titres or produce novel
natural product analogues (often r
eferred to as “metabolic engineering”)
,

is a cornerstone of the
rapidly emerging field of industrial biotechnology.




This project will exploit a highly interdisciplinary approach to elucidating and exploiting bioactive
natural product biosynthesis i
n bacteria belonging to the
Streptomyces

(and related actinobacteria)

or
Burkholderia

genera. A student working on the project will develop skills in most, if not all, of the
following: microbiology;

natural product isolation and structure elucidation;

mol
ecular genetic
manipulation; protein overproduction, purification and characterisation; enzymology;

X
-
ray
crystallography;

organic synthesis;

and a wide variety of spectroscopic methods.



We are currently investigating the biosynthetic pathways to a dive
rse array of bioactive metabolites
from such bacteria
1
-
14
, including enacyloxin IIa (antibacterial), the bottromycins (antibacterial),
methylenomycin A (antibacterial), coelimycins (antibacterial), the stambomycins (anticancer),
streptorubin B (antimalaria
l), quartromicin A (antiviral), thaxtomin A (herbicidal), desferrioxamines
(iron chelation).

The precise focus of the project will be determined by mutual agreement between
the student and the supervisors.




Key
experimental skill
s

involved
:

microbiology; natural product isolation and structure elucidation;
molecular genetic manipulation; protein overproduction, purification and characterisation;
enzymology; X
-
ray crystallography; organic synthesis; and a wide variety of spectroscopic methods


References:

1.

S.W. Haynes, P.K. Sydor, C. Corre, L. Song and G.L. Challis. Stereochemical elucidation of
streptorubin B.
J. Am. Chem. Soc.

2011
,
133
, 1793
-
1798.

2.

R. Bunet, L. Song, M.V. Mendes, C. Corre, L. Hotel, N. Rouhier, X. Framboisier, P. Leblond,
G.L.
Challis and B. Aigle
.
Characterization and manipulation of the pathway
-
specific late regulator
AlpW reveals
Streptomyces ambofaciens

as a new producer of kinamycins.
J. Bacteriol.

2011
,
193
, 1142
-
1153
.





3.

L. Laureti, L. Song, S. Huang, C. Corre, P. Leblo
nd, G.L. Challis and B. Aigle. Identification of a

bioactive 51
-
membered macrolide complex by activation of a silent polyketide synthase in
Streptomyces ambofaciens
.
Proc. Natl. Acad. Sci. USA
,
2011
,
108
, 6258
-
6263
.

4.

P.K. Sydor, S. M. Barry, O.M. Odulate
, F. Barona
-
Gomez, S.W. Haynes, C. Corre, L. Song, and G.L.
Challis.
Regio and stereodivergent antibiotic oxidative carbocyclizations catalyzed by Rieske
oxygenase
-
like

enzymes
.
Nat. Chem.

2011
,
3
, 388
-
392.

5.

C. Davis, S. Carberry, M. Schrettl, I. Singh, J.C
. Stephens, S.M. Barry, K. Kavanagh,

G.L. Challis, D.
Brougham, and S. Doyle. The role of glutathione S
-
transferase GliG in gliotoxin biosynthesis in
Aspergillus fumigatus
.
Chem. Biol.

2011
,
18
, 542
-
552.

6.

E. Mahenthiralingam, L. Song, A. Sass, J. White, C.
Wilmot, A. Marchbank, O. Boaisha, J. Paine, D.
Knight and G. L. Challis. Enacyloxins are the products of an unusual hybrid polyketide synthase
encoded by a cryptic
Burkholderia

ambifaria

AMMD gene cluster.
Chem. Biol.

2011
,
18
, 665
-
677.

7.

J.R. Whicher, G.
Florova, P.K.

Sydor, R. Singh , M. Alhamadsheh, G.L. Challis, K.A. Reynolds and
J.L. Smith.
Structure and Function of RedJ, a thioesterase from the prodiginine biosynthetic
pathway in
Streptomyces coelicolor
.
J. Biol. Chem.
2011
,
286
, 22558
-
22569.

8.

K.
Papireddy, M. Smilkstein, J. X. Kelly, Shweta, S. M. Salem, M. Alhamadsheh, S. W. Haynes, G. L
Challis, and K.A. Reynolds. Antimalarial Activity of Natural and Synthetic Prodiginines.
J. Med.
Chem
.
2011
,
54
, 5296
-
5306
.

9.

R.F. Seipke, L. Song, J. Bicz, P. Las
karis, A. Yaxley, G.L. Challis and R. Loria.
The plant pathogen
Streptomyces scabies
87
-
22 has a functional pyochelin biosynthetic pathway that is regulated by
TetR
-

and AfsR
-

family proteins.
Microbiology
,
2011
,
157
,
2681
-
2693.

10.

S. Schmelz, C.H. Botting,

L. Song, N. Kadi, G.L. Challis and J.H. Naismith. Structural basis for acyl
acceptor specificity in the achrombactin biosynthetic enzyme AcsD.
J. Mol. Biol.
2011
,
412
, 495
-
504.

11.

S. Lautru, L. Song, L. Demange, T. Lombes, H. Galons, G.L. Challis and J.
-
L. Pe
rnodet. A sweet
origin for
the key congocidine precursor 4
-
acetamidopyrrole
-
2
-
carboxylate.
Angew. Chem. Int.
Ed.
2012
,
51
,
7454
-
7458.

12.

J.
-
P. Escribano
-
Gomez, L. Song, D. J. Fox, M. J. Bibb and G. L. Challis.
Structure and biosynthesis
of the unusual polyke
tide alkaloid coelimycin P1, a metabolic product of the
cpk

gene cluster of
Streptomyces coelicolor

M145
.

Chem. Sci.

2012
,
3
,
2716
-
2720.

13.

S.M. Barry, E.R. Johnson, J.A. Kers, L. Song, P.R. Aston, B. Patel, S.B. Krasnoff
, B.R. Crane, D.M.
Gibson, R. Loria and G. L. Challis.
Cytochrome P450

catalyzed L
-
tryptophan nitration in
thaxtomin phytotoxin biosynthesis
.
Nat. Chem. Biol.

2012
,
8
,
814
-
816.

14.

J.P. Escribano
-
Gomez, L. Song, M.J. Bibb and G.L. Challis. Posttranslational

-
methylation and
macrolactamidination in the assembly of the bottromycin complex of ribosomal peptide
antibiotics.
Chem. Sci.
2012
,
3
,
3522
-
3525
.







Please state below which hazards may be connected with this studentship:



The studentship will entail work
involving:




if applies

Chemicals


high toxicity and category 1 or 2 substances

X

Organo
-
phosphate or carbamate pesticides



Skin or respiratory sensitising agents (e.g. insect parts, organic
dusts from animals, spores, pollen, antibiotics, fibres, chemical
sensitisers, wood dust etc)


X

Radionuclides


Significant manual handling


Mechanical repetition where the frequency and

duration are
significant


Working in areas where there are temperature extremes

X

Driving vehicles (tractors, fork lifts, ATVs etc)


Crop planting, harvesting, recording or grading


Working in close proximity to bees or other stinging insects


Working at height [>2 m] (using various types of access
equipment)


Working with noisy or vibrating equipment


Working at night (between 11.00pm and 6.00am)


Food handling



Other significant hazards (specify)