The Goss lab

rjmg
Thursday 8 September 2022


Research Centre:



Group Highlights


Our group’s research includes a diverse array of projects within the field of chemical biologywith natural productsas the focus. We are particularly interested in understanding biosynthetic processes and the application of the powerful combination of synthetic biology and organic synthesisto harness and redesign these systems, creating new biosynthetic pathways. We are interested in the manipulation of individual enzymes and biosynthetic pathways as an expeditious tools for synthesising designer “natural” product analogues of medicinal value. The rapid access to libraries of natural products, that biosynthetic manipulation can afford, is useful for gaining a greater understanding of the exact molecular mode of action of drug molecules.

We are interested in understanding biosynthetic processes at the molecular level and combining the tools of organic synthesis, molecular biology and protein biochemistry to generate new natural products of our own design (Fig 1). This research has been recognized through several prestigious awards.

There are 4 main complementary and overlapping research projects ongoing within our group:

  1. Harnessing Biosynthesisto Generate New to Nature Natural Products, Including the new approach of GenoChemeticsthat we have pioneered
  2. Biosynthetic Elucidation: We are particularly intrigued by medicinally relevant and biosynthetically exotic natural products, and in determining the chemistry, enzymology and genetic programming that underpins their assembly.
  3. Discovering and Developing Enzymes for Use in Synthesis

(Including our engineered plug- and-play biocatalytic biofilm platform for use in flow chemistry) Biotransormations

  1. Natural Product Discovery(with a particular focus on finding new antibiotics with novel scaffolds and clinically unexploited modes of action) – we employ state-of-the-art approaches and discovery is directed by combining genome reading, metabolomics and bioactivity assessment.

Our lab website: https://rjmg.wp.st-andrews.ac.uk/



Research


Our group’s research includes a diverse array of projects within the field of chemical biology with natural products as the focus.

There are 4 main complementary and overlapping research projects ongoing within our group:

  1. Biosynthetic Elucidation: We are particularly intrigued by medicinally relevant and biosynthetically exotic natural products, and in determining the chemistry, enzymology and genetic programming that underpins their assembly.
  2. Harnessing Biosynthesis To Generate New to Nature Natural ProductsNatural products, compounds generated by living organisms, play a critical role in medicine. Over 60% of anticancer agents and over 70% of antibiotics are based on natural products. The generation of analogues of these compounds is critical in order to probe the identity and nature of the targets, determine a compound’s mechanism of action, explore structure activity relationships and develop designer compounds with improved activities an bioavailability.

By blending together synthetic biology and synthetic chemistry we are able to expeditiously access analogues of structurally complex natural products which would other wise be hard to access using synthesis alone.

 

 

Our approaches to analogue generation include precursor-directed biosynthesis, mutasynthesis, semi-synthesis, total synthesis and a new approach that we have pioneered called GenoChemetics.

            GenoChemetics– a new paradigm in natural product analogue generation

            In this powerful approach, a gene, encoding a reactive and selectively chemically modifiable handle, is introduced into an organism to act in concert with an existing biosynthetic pathway. By developing mild reaction methodologies, we can selectively derivitise the natural product without the need to employ protecting group strategies.

Gene Insertion enables Selective Chemical Modification

 We have developed a new approach to enable the manipulation of biosynthetic pathways. By introducing a gene to act in concert with an existing biosynthetic pathway we have installed a handle enabling selective chemical modification of the natural product.

Modification at this handle affords the potential to selectively ligate or immobilise the unnatural product. We plan to extend this concept further by genetically introducing other chemical handles.

  1. Natural Product Discovery (with a particular focus on finding new antibiotics with novel scaffolds and clinically unexploited modes of action) – we employ state-of-the-art approaches and discovery is directed by combining genome reading, metabolomics and bioactivity assessment.

We look in environmentally unusual niches in order to find unique chemistries and enzymologies.

  1. Discovering and Developing Enzymes for Use in Synthesis

(Including our engineered plug- and-play biocatalytic biofilm platform for use in flow chemistry)

Developing biotransformations for organic synthesis

Oftentimes the employment of an enzyme as part of a synthesis can significantly aid efficiency.

A key interest within our group is the development of biotransformations that may be readily uptaken by main-stream organic chemists who would normally be reluctant to employ enzymatic approaches. Our convenient approach to generating tryptophan analogues is being gradually embraced by a number of major synthetic chemistry groups across the world including the Ley group in Cambridge.

We are developing simple biotransformations to enable access to a variety of unnatural amino acids and to nucleoside analogues (In funded collaboration with GSK, Stevenage). Our work on discovering and developing new unusual halogenases as tools for bioctalysis and synthetic biology has attracted funded collaboration with AZ and Syngenta.

In complement to our biocatalyst discovery and development programmes we have developed a method of engineering biofilms of recombinant microorganisms in order to make robust biocatalysts of as potential components of flow chemistry. The engineered biofilm is considerably more robust and catalytically active than the immobilised enzyme or the natural biofilm (fig. 8). This platform has the potential to be used as a plug and play system into which genes encoding a biotransformation of choice may be introduced. Excitingly, we have recently demonstrated that the enzyme catalyst is rapidly and completely regenerated within the biocatalyic biofilm, affording biocatalytic longevity and the tantalising prospect of using gene switching to change the biofilms catalytic function.

 

 

 

 

 

 

 

Figure 2 Top Left: natural biofilm after 6 days, Bottom Left: significantly more mature and more stable engineered biofilm after 6 days. Right Hand Side: conversion of haloindole to halotryptophan; reaction profile for (i) 5-fluoroindole (biofilm) (ii a) 5-chloroindole (biofilm), (ii b) 5-chloroindole (immobilised enzyme), (ii c) 5-chloroindole (incubated with twice the biomass of free cells) (iii) 5-bromoindole (biofilm).

 

Group Members


Sunil Sharma

I am a synthetic/ medicinal chemist with an interest in synthesis of bioactive molecules and analytical tools for biochemical processes. My research interests include total synthesis of natural products, multi-step organic synthesis and development of bio-analytical methods. I am familiar pharmacophore based ligand design, SAR/QSAR analysis and bioassays using in vitro enzyme screenings. My experience includes synthesis design and commercialisation on multinational collaborative projects involving biologists, IP experts and marketing. I have significant experience in project/ laboratory management, supervision and training of research student, teaching and demonstrating chemistry practical to undergraduate students.

Sunil Sharma’s CV

Helen Connaris

An experienced group leader and manager of research projects and teams in academia and in SME, with focus on developing novel non-antibody protein therapeutics for application in disease. Strongly motivated individual to find biological solutions to existing biological problems, particularly in the area of health. An assertive but conscientious team player with experience in delivering projects to specific timelines.

Helen Connaris’s CV

Rosemary Lynch

I am a synthetic/medicinal chemist with extensive experience in biotech and pharma now expanding my skill set in the areas of molecular biology and synthetic biology, towards diversification of natural products of medicinal interest. 

Rosemary Lynch’s CV

Yunpeng Wang

I am a highly motivated synthetic biology researcher with keen interest in promoter engineering, pathway modification and compounds production using synthetic biology methods and protein expression and purification. As a researcher in molecular biology, metabolic engineering, and synthetic biology I have valuable experience in production of small molecules and natural products through introduction and engineering of pathways. I have experience in elevating production titres using pathway and promotor engineering. I also have skills in protein production and purification. I have expertise in both LC and LCMSMS analysis which I apply to both metabolomics and natural product identification.

Yunpeng Wang’s CV

Ying Zhang

I am a PhD student in Goss group and focusing on finding new Flavin Dependent Halogenases (FDHs). I have expertise in bioinformatics, heterologous expression and protein production

Through my MSc I have developed skills in microorganism cultivation including isolating and identifying poisonous microbes and general molecular biology techniques, cloning work (total RNA isolation-cDNA reverse transcription-DNA reproducing), Sugar content detection in fresh fruit using HPLC.

I am motivated, highly-efficient and have great communication skills, I am able to work under pressure independently and have team spirit.

Ying Zhang’s CV

David Alexander Burnett

 

I am a biochemist with research interests in the production and development of plant virus based nanotechnologies. As a PhD student at the University of St Andrews my project focuses on the development of enzyme coated nanoparticles derived from plant virus capsid proteins. I aim to develop a system capable of presenting enzymatic pathways on stable and re-usable particles with the hope of being able to produce these pathways on a particle on a large scale. 

David Alexander Burnett’s CV

Samuel Molyneux

As a current PhD student in the Goss group, my interests lie in catalysis, both synthetic organic chemistry and enzymatic systems.My PhD research is focussed on developing aqueous cross coupling methodologies to be merged with biosnynthetic organohalide generated using novel halogenases enzymes- this means and skills lie in synthetic organic chemistry, utilising bioinformatical tools to search for novel proteins, and enzyme production, purification, and analysis. 

Samuel Molyneux’s CV

Camiel Leake

I am a highly motivated final-year MChem Student at the university of St Andrews. I have recently joined the Goss group as part of my final year research project where I have been utilising a bioinformatics approach to discover new flavin dependent halogenases. Between 2019 and 2020 I completed a 12 month long industrial placement at Roche Basel where I worked on two different projects and gained invaluable synthetic skills as well as a deeper and broader understanding of organic synthesis. I am currently motivated and looking for PhD positions with an emphasis on organic synthesis with applications to medicinal chemistry and biology. 

Camiel Leake’s CV

Scarlet Ferrinho

 

I am currently a PhD student at the University of St Andrews. My undergraduate degree in biomolecular science bridged the divide between chemistry and biology in a like manner to my PhD. Working with both category I and II microorganisms means I have excellent aseptic technique. Furthermore, I am competent in microbiology techniques in addition to synthetic and analytical chemistry. I am skilled in the identification, production, isolation and characterisation of natural products, as well as the production and purification of proteins.

Scarlet Ferrinho’s CV

Alan Obled

I am an organic chemist with research interests in the modification of natural products. Specifically, my research focuses on natural products with medicinal properties. As a CRITICAT CDT student, my projects involve conducting catalytic reactions, using homogenous catalysis and biocatalysis in order to obtain analogues of the target natural products, and then screening their bioactivities, particularly antibiotic properties against a variety of bacteria. My research endeavours on harnessing the power of Biosynthesis to produce complex and bio-active metabolites possessing orthogonal reactive handles that can then be diversified using the flexibility of Chemistry.

Alan Obled’s CV

Gemma Fisher

I am a PhD Student jointly supervised by Dr Rafael da Silva and Professor Rebecca Goss. My PhD is part of the EASTBIO Doctoral Training Partnership and falls under the theme of industrial biotechnology and bioenergy. My research will elucidate the mechanism of Psychrobacter arcticus ATP phosphoribosyltransferase with the aim to generate opportunities for protein engineering. ATP phosphoribosyl transferase is the first enzyme of the histidine biosynthetic pathway. The goal of this project is development of ATP phosphoribosyltransferase suitable for industrial application.

Gemma Fisher CV

Publications

Chapters

Modern developments in biocatalysis
Ferrinho, S. A., Molyneux, S. A., Goss, R. J. M., Bell, E. L., Crossley, A., Green, A. P., Yeow, K. & O’Reilly, E., 1 Mar 2023, Modern developments in catalysis. Hutchings, G. J., Davidson, M., Catlow, R., Hardacre, C., Turner, N., Williams, C., Mulholland, A., Goodall, J. & Mitchell, C. (eds.). London: World Scientific, Vol. 2. p. 535-594 60 p. (Modern developments in catalysis).
Research output: Chapter in Book/Report/Conference proceedingChapter

Natural products incorporating pyrimidine nucleosides
Michailidou, F., Burnett, D. A., Sharma, S. V., Van Lanen, S. & Goss, R., 20 Feb 2020, (E-pub ahead of print) Reference module in chemistry, molecular sciences and chemical engineering. Elsevier Inc.
Research output: Chapter in Book/Report/Conference proceedingEntry for encyclopedia/dictionary

 

Articles

The identification and heterologous expression of the biosynthetic gene cluster encoding the antibiotic and anticancer agent marinomycin
Abraham, E., Lawther, H., Wang, Y., Zarins-Tutt, J. S., Rivera, G. S., Wu, C. C., Connoly, J., Florence, G. J., Agbo, M. O., Gao, H. & Goss, R., 16 Jan 2024, In: Biomolecules. 14, 1, 11 p., 117.
Research output: Contribution to journalArticlepeer-review

Artificial intelligence for natural product drug discovery
Mullowney, M. W., Duncan, K. R., Elsayed, S. S., Garg, N., van der Hooft, J. J. J., Martin, N. I., Meijer, D., Terlouw, B. R., Biermann, F., Blin, K., Durairaj, J., Gorostiola González, M., Helfrich, E. J. N., Huber, F., Leopold-Messer, S., Rajan, K., de Rond, T., van Santen, J. A., Sorokina, M., Balunas, M. J., & 38 othersBeniddir, M. A., van Bergeijk, D. A., Carroll, L. M., Clark, C. M., Clevert, D-A., Dejong, C. A., Du, C., Ferrinho, S., Grisoni, F., Hofstetter, A., Jespers, W., Kalinina, O. V., Kautsar, S. A., Kim, H., Leao, T. F., Masschelein, J., Rees, E. R., Reher, R., Reker, D., Schwaller, P., Segler, M., Skinnider, M. A., Walker, A. S., Willighagen, E. L., Zdrazil, B., Ziemert, N., Goss, R. J. M., Guyomard, P., Volkamer, A., Gerwick, W. H., Kim, H. U., Müller, R., van Wezel, G. P., van Westen, G. J. P., Hirsch, A. K. H., Linington, R. G., Robinson, S. L. & Medema, M. H., Nov 2023, In: Nature Reviews Drug Discovery. 22, p. 895-916
Research output: Contribution to journalReview articlepeer-review

Fully aqueous and air-compatible cross-coupling of primary alkyl halides with aryl boronic species: a possible and facile method
Molyneux, S. & Goss, R., 5 May 2023, In: ACS Catalysis. 13, 9, p. 6365-6374 10 p.
Research output: Contribution to journalArticlepeer-review

The impact of viral infection on the chemistries of the Earth’s most abundant photosynthesisers: metabolically talented aquatic cyanobacteria
Wang, Y., Ferrinho, S., Connaris, H. & Goss, R., 4 Aug 2023, In: Biomolecules. 13, 8, 29 p., 1218.
Research output: Contribution to journalArticlepeer-review

An expedient, mild and aqueous method for Suzuki–Miyaura diversification of (hetero)aryl halides or (poly)chlorinated pharmaceuticals
Sharma, S. V., Pubill-Ulldemolins, C., Marelli, E. & Goss, R. J. M., 21 Oct 2021, In: Organic Chemistry Frontiers. 8, 20, p. 5722-5727
Research output: Contribution to journalArticlepeer-review

Antiviral drug discovery: preparing for the next pandemic
Adamson, C. S., Chibale, K., Goss, R., Jaspars, M., Newman, D. J. & Dorrington, R. A., 1 Feb 2021, (E-pub ahead of print) In: Chemical Society Reviews. Advance Article, 9 p.
Research output: Contribution to journalReview articlepeer-review

GenoChemetic strategy for derivatization of the violacein natural product scaffold
Lai, H-E., Obled, A. M. C., Chee, S. M., Morgan, R. M., Lynch, R., Sharma, S. V., Moore, S. J., Polizzi, K. M., Goss, R. J. M. & Freemont, P. S., 14 Oct 2021, (E-pub ahead of print) In: ACS Chemical Biology. Articles ASAP, 8 p.
Research output: Contribution to journalArticlepeer-review

Halogenases: a palette of emerging opportunities for synthetic biology–synthetic chemistry and C–H functionalisation
Crowe, C., Molyneux, S., Sharma, S. V., Zhang, Y., Gkotsi, D. S., Connaris, H. & Goss, R. J. M., 7 Sept 2021, In: Chemical Society Reviews. 17, 50, p. 9443-9481 39 p.
Research output: Contribution to journalReview articlepeer-review

SynBio-SynChem approaches to diversifying the pacidamycins through the exploitation of an observed Pictet-Spengler reaction
Cartmell, C., Abou Fayad, A., Lynch, R., Sharma, S., Hauck, N., Gust, B. & Goss, R. J. M., 15 Feb 2021, In: ChemBioChem. 22, 4, p. 712-716 6 p.
Research output: Contribution to journalArticlepeer-review

Nicotiana benthamiana as a transient expression host to produce auxin analogs
Davis, K., Gkotsi, D. S., Smith, D. R. M., Goss, R. J. M., Caputi, L. & O’Connor, S. E., 20 Nov 2020, In: Frontiers in Plant Science. 11, 9 p., 581675.
Research output: Contribution to journalArticlepeer-review

 

Other publications

SynBio: Green and clean sustainable solutions for designer pharmaceuticals, catalysis, and bioremediation
Goss, R., Connolly, J. & Sadler, J., Oct 2020, In: Current opinion in chemical biology. 58, p. A1-A3
Research output: Contribution to journalEditorialpeer-review

Analysis and optimisation of the physiology of engineered biofilms for biotransformations
Leech, J. T., Vizcaino-Caston, I., Barberi, T., Goss, R., Simmons, M. & Overton, T., 10 Jul 2014, In: New Biotechnology. 31, p. S86-S86 1 p.
Research output: Contribution to journalAbstractpeer-review

ENZYMOLOGY A radical finding
Goss, R. J. M. & Grueschow, S., Nov 2014, In: Nature Chemical Biology. 10, 11, p. 878-879 2 p.
Research output: Contribution to journalComment/debatepeer-review

SIMPLE AND SCALABLE ACCES TO L-7-HALOTRYPTOPHANS AND OTHER L-HALOTRYPTOPHANS THROUGH AN IMPROVED ONE-POT BIOTRANSFORMATION
Willemse, T., Smith, D. R. M., Gkotsi, D., Schepens, W., Maes, B. U. W., Ballet, S. & Goss, R. J. M., Sept 2014, In: Journal of Peptide Science. 20, p. S143-S144 2 p.
Research output: Contribution to journalAbstractpeer-review

Elucidating and exploiting biosynthesis
Goss, R. J. M., 28 Aug 2011, In: Abstracts of Papers of the American Chemical Society. 242, 1 p.
Research output: Contribution to journalAbstractpeer-review

New unnatural products by harnessing biosynthesis
Goss, R. J. M., 22 Aug 2010, In: Abstracts of Papers of the American Chemical Society. 240, 1 p.
Research output: Contribution to journalAbstractpeer-review

FLUO 13-Novel halogenated natural products from actinomycetes
Goss, R. J. M., 17 Aug 2008, In: Abstracts of Papers of the American Chemical Society. 236, 1 p.
Research output: Contribution to journalAbstractpeer-review

 



Contact

Rebecca can be contacted by email [email protected] or by post to the address below:

Rebecca Goss
School of Chemistry
BMS Building, North Haugh
St Andrews
KY16 9ST
United Kingdom

Informal enquiries relating to research opportunities are welcomed.



Related themes:

Related Centre: