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‘Omics’ of natural products and redox biology
Editorial overview
Pieter C Dorrestein and Kate S Carroll
Current Opinion in Chemical Biology 2011, 15:3–4
1367-5931/$ – see front matter
# 2011 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.cbpa.2011.01.009
Pieter C Dorrestein1,2,3
1
Skaggs School of Pharmacy and
Pharmaceutical Sciences, Biomedical
Science Building (BSB), 9500 Gilman Drive,
MC 0636, La Jolla, CA 92093-0636, United
States
2
Department of Chemistry and Biochemistry,
Biomedical Science Building (BSB), 9500
Gilman Drive, MC 0636, La Jolla, CA 920930636, United States
3
Department of Pharmacology, Biomedical
Science Building (BSB), 9500 Gilman Drive, MC
0636, La Jolla, CA 92093-0636, United States
e-mail: pdorrestein@ucsd.edu
Pieter C Dorrestein is an associate professor at the
University of California, San Diego. He received his PhD in
chemical biology from Cornell University (mentored by
Tadgh Begley, 2004) and was an NRSA postdoctoral
fellow at the University of Illinois, Urbana-Champaign
(sponsored by Neil Kelleher and co-sponsored by
Christopher Walsh). In September 2006, he started his
position as an assistant professor in the Skaggs School of
Pharmacy and Pharmaceutical Sciences and the
departments of pharmacology, chemistry and
biochemistry and was promoted to associate professor in
July 2010. He is also a member of the center for marine
biotechnology and biomedicine and the UCSD center for
computational mass spectrometry. His research interests
are in the development of mass spectrometry
applications that aid in the analysis of the biosynthesis of
small molecules, the characterization of post-translational
modifications and is investigating how populations of
organisms and cells use small molecules as signals of
survival in the presence of neighboring organisms.
Kate S Carroll
The Scripps Research Institute, Department
of Chemistry, 130 Scripps Way 2B2, Jupiter,
FL 33458, United States
e-mail: kcarroll@scripps.edu
Kate S Carroll is an associate professor in the department of
chemistry at The Scripps Research Institute in Jupiter,
Florida. She received her BA degree in biochemistry from
Mills College in 1996 and PhD in biochemistry from Stanford
University in 2003. Her postdoctoral work was completed at
the University of California, Berkeley, where she was a
Damon Runyon-Walter Winchell Chancer Fund Fellow with
Prof. Carolyn Bertozzi. She was an assistant professor at the
University of Michigan until 2010, when she joined the
chemistry faculty at Scripps. Her research interests span the
disciplines of chemistry and biology with an emphasis on
studies of sulfur metabolism pertinent to disease states. Her
laboratory focuses on the development of novel tools to
study redox modifications of cysteine thiols, profiling
changes in protein oxidation associated with disease, and
exploiting this information for the development of diagnostic
and therapeutic approaches. In addition, her group
investigates sulfur pathways that are essential for infection
and long-term survival of human pathogens such as
Mycobacterium tuberculosis. She has received the Camille
Dreyfus Teacher-Scholar Award (2010), the Scientist
Development Award from the American Heart Association
(2008), and the Special Fellow Award from the Leukemia
and Lymphoma Society (2006).
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The past issues of ‘Omics’ in Current Opinion in Chemical Biology have
highlighted the advances in metabolomic and proteomic technologies. In
line with the guest editors’ own research interests, this ‘Omics’ issue of
Current Opinion in Chemical Biology highlights two emerging areas where
the large-scale and system-wide analysis of biology is beginning to play a
significant role. These exciting areas are the integration of ‘omics’ into the
discovery and function of non-primary metabolite small molecules and the
global analysis of redox biology. We highlight these areas as advances in both
areas have significant translational impact and will continue to shape future
medicine.
Natural products are involved in metabolic exchange processes including
cell-to-cell communication, growth promoters, nutrient scavengers, protection or induction of oxidative damage and cell differentiation (e.g. retinoic
acid in stem cell differentiation). Our foundation of modern medicine sits on
natural products. Examples of natural products that have shaped modern
medicine include Taxol (anticancer), Penicillin (antibiotic), Rapamycin
(immunosuppressant) and Lovastatin (cholesterol lowering). Perhaps just
as important is that such molecules define cellular functions of living
organisms and that there is a need for strategies to efficiently identify their
functions.
In this issue of Current Opinion in Chemical Biology three omic areas in
natural products are highlighted. They are the ‘omic’ based mining of
natural products, new methods for characterizing natural products and
strategies that elucidate the mechanisms by which such natural products
function. The application of ‘omics’ technologies, in silico genome mining,
metabolomics and proteomic tools is leading to new sources of natural
products to be investigated such as the human parvome, a new term for the
collection of all non-primary metabolite small molecules produced by an
organism introduced to us by Julian Davies, for the discovery of new
therapeutics including urgently needed antibiotics. Using in silico genome
mining, van der Donk and colleagues highlight that only a fraction of
ribosomally natural products have been characterized and Hertweck highlights the strategies by which microbial genomes are mined for novel natural
products and the Wang laboratory describes the novel mechanisms by which
silent and orphan gene clusters responsible for the production of these small
molecules can be activated at the genomic level. The articles in this issue
highlight the need for the development of new technologies and platforms
to efficiently characterize natural products; to this effect Schroeder describes
novel NMR-based technologies to structurally natural products from crude
mixtures and the Burkart laboratory highlights how new proteomic tools
enable the characterization of polyketide and non-ribosomal peptide natural
products biosynthetic motifs even in vivo. One of the most challenging
aspects in natural product investigations is the ability to determine how they
function and what their targets are. Osada describes how this is accomplished using proteomic approaches while Boone describes how this is
Current Opinion in Chemical Biology 2011, 15:3–4
4 Omics
accomplished using system-wide network analysis with
yeast chemical genomic approaches. To finalize the issue
Jane Yang, Jessica Karr and Jeramie Watrous from the
Dorrestein laboratory have highlighted the importance of
small microbial derived molecules in human health and
how ‘omic’ tools should be combined to mine natural
products from microbiomes to understand their roles in
health and disease.
The other emerging area in chemical biology of translational importance is redox biology. Oxidative/nitrosative
damage by reactive species plays a central role in the
pathogenesis of many human diseases including cancer
and is also important to a broad range of biological
responses in microorganisms, plants and other animals.
However, in many cases, reactive oxygen and nitrogen
species are also important signaling molecules that are
used in healthy cells to regulate normal functions such as
vascular smooth muscle tone, insulin and growth factor
signaling. This issue therefore highlights the recent
advances to characterize redox cycles in biological systems at an omic scale. Along these lines, oxidative
cysteine modifications have emerged as a central mechanism for dynamic post-translational regulation of all
major protein classes and correlate with many disease
states. Elucidating the precise roles of cysteine oxidation
in physiology and pathology presents a major challenge.
Several articles in this issue are devoted to developments
in the field of redox proteomics. To begin this section,
Leonard and Carroll provide an overview of oxidative
cysteine modifications as well as recent advances in
chemical methods for detection. Jones and Young-Mi
Go highlight the cysteine proteome and discuss key
features that distinguish redox-signaling from redox-sen-
Current Opinion in Chemical Biology 2011, 15:3–4
sing thiols. Thamsen and Jakob expand on the theme of
wide-scale proteomic analysis of cellular redox networks
in prokaryotic and eukaryotic organisms. The review by
Murphy and colleagues covers strategies to characterize
protein thiol modifications and emphasizes orthogonal
techniques for understanding how reactive molecules
may contribute to signaling and damage. Seth and
Stammler highlight biological aspects of protein S-nitrosylation and present classification schemes for denitrosylases and protein S-nitrosylases. The review by Wang and
Xian focuses on recent progress in chemical methods to
detect S-nitrosation. Cysteine residues in proteins also
play a central role in coordinating metal cofactors. In this
light, Shi and Chance discuss forward and reverse
approaches to metalloprotein discovery and characterization. In addition to cysteine-based regulation of protein
function, various secondary metabolites from plants, bacteria and fungi are redox-active molecules that modulate
intracellular redox equilibrium in living cells. Jacob and
colleagues highlight some key examples of such redoxmodulating metabolites and describe how their properties
might be harnessed to treat cancer and autoinflammatory
diseases. There is growing evidence that redox homeostasis is dysregulated in many disease states and this
biochemical feature may offer new venues for therapeutic
intervention. The article by Tew and Townsend
describes recent advances in redox platforms for cancer
drug discovery and how defining the ‘glutathionome’ may
also provide opportunities for new target identification.
Hur and Gray highlight small-molecule inducers of the
antioxidant response pathway and their biological activities in cellular models. Finally, the review by Johnston
discusses new strategies to identify redox-cycling compounds using high-throughput screening approaches.
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