Christopher J Paddon

Christopher J Paddon
Amyris · Commercial

Ph.D.

About

54
Publications
13,793
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5,428
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Introduction
Heterologous production of isoprenoids; Valorization of industrial fermentation 'waste'; Development of industrially scaleable isoprenoid vaccine adjuvants.
Skills and Expertise

Publications

Publications (54)
Article
Full-text available
The antimalarial drug artemisinin is a natural product produced by the plant Artemisia annua. Extracts of A. annua have been used in Chinese herbal medicine for over two millennia. Following the re-discovery of A. annua extract as an effective antimalarial, and the isolation and structural elucidation of artemisinin as the active agent, it was reco...
Article
Development of a cost-effective process for the production of artemisinin, the precursor of all artemisinin-derived drugs, the first-line treatment for malaria, has been a long pursued endeavor. The breakthrough achievement of coaxing genetically engineered yeast to express Artemisia annua genes for the commercial production of artemisinic acid, an...
Article
Full-text available
The antimalarial drug artemisinin and the specialty chemical β-farnesene are examples of natural product isoprenoids that can help solve global challenges, but whose usage has previously been limited by supply and cost impediments. This review describes the path to commercial production of these compounds utilizing fermentation of engineered yeast....
Article
Terpenoids comprise a large (>55000) family of compounds, very few of which have been used commercially due to low and economically unpractical production in their native hosts (generally plants and microorganisms). Two examples of natural terpenoid production are described (rubber and astaxanthin), but the advent of metabolic engineering has allow...
Article
Recent developments in synthetic biology, combined with continued progress in systems biology and metabolic engineering, have enabled the engineering of microorganisms to produce heterologous molecules in a manner that was previously unfeasible. The successful synthesis and recent entry of semi-synthetic artemisinin into commercial production is th...
Article
Full-text available
In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties,...
Chapter
Artemisinin is a sesquiterpene lactone endoperoxide with potent antimalarial properties, recommended by the World Health Organization for the treatment of malaria in artemisinin combination therapies (ACTs). It is extracted from the plant Artemisia annua, but its supplies are limited and its price is volatile. In order to increase supply and stabil...
Article
Full-text available
Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S28...
Data
Full-text available
Figure S5. Multiple sequence alignment of Snf11p and Swi1p.
Data
Full-text available
Figure S2. Chromosome separation gel with RDL1 and PHO12 probed.
Data
Table S5. Mutations found in genes in the cAMP signaling pathway.
Data
Full-text available
Figure S4. Differences between CEN.PK113-7D and S288C in the MAPK signaling pathway.
Data
Table S3. Indels in genes in CEN.PK113-7D compared to S288C.
Data
Table S1. Repetitive transposon sequences were hard to assemble from whole genome shotgun data. Evidence of transposons was obtained in two ways. First, depth-of-coverage of CEN.PK113-7D and S288C reads on Ty retrotransposons sequences in the S288C genome was analysed. The number of retrotransposons was estimated from these ratios. Second, evidence...
Data
Table S4. Mutations in the galactose uptake and ergosterol biosynthesis pathways compared to the SNVs found previously in CEN.PK113-7D [35].
Data
Figure S3. Chromosome separation gel with contig151 probed.
Data
Full-text available
Figure S1. Analysis of transposon composition by alignment of the CEN.PK113-7D and S288c genomes. When an S288c transposon is not present in CEN.PK113-7D it results in a gapped alignment (GA) of about 6 Kbp. Transposons that are present can cause contig breaks (CB) in the assembly. Only YCLWTy5-1 was fully assembled (AS).
Data
Table S2. SNVs in genes in CEN.PK113-7D compared to S288C.
Data
Table S7. S. cerevisiae with an assembled genome deposited in GenBank. The classification assigned in the 'group' column was used to generate Figure 8.
Data
Table S6. List of deleted genes, which is defined as not having a homologous hit in the CEN.PK113-7D genome for at least 95% and having a CEN.PK113-7D/S288c log2 ratio of less then -0.6. The PMR2 locus has a blue background color.
Article
Full-text available
Malaria, caused by Plasmodium sp, results in almost one million deaths and over 200 million new infections annually. The World Health Organization has recommended that artemisinin-based combination therapies be used for treatment of malaria. Artemisinin is a sesquiterpene lactone isolated from the plant Artemisia annua. However, the supply and pric...
Article
Full-text available
Background Artemisinin derivatives are the key active ingredients in Artemisinin combination therapies (ACTs), the most effective therapies available for treatment of malaria. Because the raw material is extracted from plants with long growing seasons, artemisinin is often in short supply, and fermentation would be an attractive alternative product...
Article
Full-text available
Due to the global occurrence of multi-drug-resistant malarial parasites (Plasmodium falciparum), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (Artemisia annua). However, artemisinin is in short supply and unaffordable to most malaria patien...
Conference Paper
Malaria threatens 350-500 million lives every year, with over 1 million deaths, primarily children under the age of five. Artemisinin based Combination Therapies (ACT's) are recommended by World Health Organization for the treatment of uncomplicated malaria. Although currently more costly than traditional drug treatments, ACT's are preferred since...
Data
A list of genes significantly differentially expressed in EPY330 or EPY338. The additional data file includes a processed data set for differentially expressed genes identified by microarray analysis. The data set has 2,156 genes that were significantly differentially expressed in at least one experimental time points and has 488 and 256 genes that...
Article
Engineering biosynthetic pathways in microbes for the production of complex chemicals and pharmaceuticals is an attractive alternative to chemical synthesis. However, in transferring large pathways to alternate hosts and manipulating expression levels, the native regulation of carbon flux through the pathway may be lost leading to imbalances in the...
Article
Full-text available
Bacillus subtilis exhibits a complex adaptive response to low levels of peroxides. We used global transcriptional profiling to monitor the magnitude and kinetics of changes in the mRNA population after exposure to either hydrogen peroxide (H2O2) or tert-butyl peroxide (t-buOOH). The peroxide stimulons could be largely accounted for by three regulon...
Article
Full-text available
The Bacillus subtilis extracytoplasmic function (ECF) sigma factor sigma(W) controls a large regulon that is strongly induced by alkali shock. To define the physiological role of sigma(W) we have sought to identify the complete set of genes under sigma(W) control. Previously, we described a promoter consensus search procedure to identify sigma(W) c...
Article
Full-text available
In response to heat stress, Bacillus subtilisactivates the transcription of well over 100 different genes. Many of these genes are members of a general stress response regulon controlled by the secondary sigma factor, ςB, while others are under control of the HrcA or CtsR heat shock regulators. We have used DNA microarrays to monitor the global tra...
Article
The expression of mammalian G protein coupled receptors (GPCRs) in S. cerevisiae provides a powerful assay system for functional analysis, ligand identification and pharmaceutical screening. However, relatively few receptors have been coupled to the pheromone response pathway via the yeast G(alpha), Gpa1p, or chimeric yeast/mammalian G(alpha) subun...
Article
Wild-type yeast Saccharomyces cerevisiae are surprisingly resistant to a wide range of drugs and agents. We had previously isolated novobiocin-sensitive mutants to aid the study of the intracellular target for this drug. Characterization of one of these mutants, mds1, revealed that it was sensitive not only to novobiocin but also to a wide range of...
Article
Full-text available
We have extended the technique of PCR-directed recombination in Saccharomyces cerevisiae to develop a simple method for plasmid or gene construction in the absence of suitable restriction sites. The DNA to be cloned is PCR-amplified with 30–40 bp of homology to a linearized yeast plasmid. Co-transformation into yeast results in homologous recombina...
Article
The use of yeast as a model system to study mammalian proteins is attractive, because yeast genetic tools can be utilized if a suitable phenotype is created. STE6, the Saccharomyces cerevisiae a-factor mating pheromone transporter, and CFTR, the mammalian cystic fibrosis transmembrane conductance regulator, are both members of the ATP binding casse...
Article
Full-text available
Phosphorylation of eukaryotic translation initiation factor 2 (eIF-2) in amino acid-starved cells of the yeast Saccharomyces cerevisiae reduces general protein synthesis but specifically stimulates translation of GCN4 mRNA. This regulatory mechanism is dependent on the nonessential GCN3 protein and multiple essential proteins encoded by GCD genes....
Article
Phosphorylation of eukaryotic translation initiation factor 2 (eIF-2) in amino acid-starved cells of the yeast Saccharomyces cerevisiae reduces general protein synthesis but specifically stimulates translation of GCN4 mRNA. This regulatory mechanism is dependent on the nonessential GCN3 protein and multiple essential proteins encoded by GCD genes....
Article
Full-text available
The GCD2 protein is a translational repressor of GCN4, the transcriptional activator of multiple amino acid biosynthetic genes in Saccharomyces cerevisiae. We present evidence that GCD2 has a general function in the initiation of protein synthesis in addition to its gene-specific role in translational control of GCN4 expression. Two temperature-sen...
Article
The GCD2 protein is a translational repressor of GCN4, the transcriptional activator of multiple amino acid biosynthetic genes in Saccharomyces cerevisiae. We present evidence that GCD2 has a general function in the initiation of protein synthesis in addition to its gene-specific role in translational control of GCN4 expression. Two temperature-sen...
Article
Full-text available
GCD12 encodes a translational repressor of the GCN4 protein, a transcriptional activator of amino acid biosynthetic genes in the yeast Saccharomyces cerevisiae. gcd12 mutations override the requirement for the GCN2 and GCN3 gene products for derepression of GCN4 expression, suggesting that GCN2 and GCN3 function indirectly as positive regulators by...
Article
Full-text available
The GCD2 gene product is required in conditions of amino acid sufficiency to repress the synthesis of GCN4, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. GCD2 is also required unconditionally for cell viability. The constitutive derepression of GCN4 expression and temperature sensitivity for growth associ...
Data
Data kindly reviewed (20-SEP-1989) by Paddon C.
Article
Full-text available
Bacillus amyloliquefaciens extracellular RNase has been previously cloned and expressed in Bacillus subtilis. Site-specific mutagenesis experiments have identified codon -39 as the start site of translation. We have determined the primary signal peptide cleavage site of preprobarnase and propose a pathway for the conversion of probarnase to mature...
Article
An inactivated gene for Bacillus amyloliquefaciens extracellular ribonuclease (barnase) has previously been cloned and sequenced following transposon mutagenesis. The intact gene could not be assembled in Escherichia coli and is presumed to be lethal. Therefore, we introduced specific mutations into the barnase gene to prevent its lethal effect. A...
Article
The plasmid pTV1, constructed in Bacillus subtilis as a tool for insertional mutagenesis by the transposon Tn917, has been transferred to Bacillus amyloliquefaciens by transduction with the phage PBS1. Insertional mutants containing Tn917 were observed in the new host. Southern blot analysis of such mutants indicated no preference for insertion sit...
Article
The gene for Bacillus amyloliquefaciens extracellular RNase (barnase) has been cloned in an inactive form in Escherichia coli following insertional mutagenesis by transposon Tn917. The nucleotide (nt) sequence of the gene was determined and the deduced amino acid (aa) sequence found to correspond almost precisely to the previously determined sequen...
Article
All enzymes of the citric acid cycle were found to be present in cell-free extracts of the facultative methylotroph Arthrobacter 2B2 except 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase. The dehydrogenase (E1) and lipoamide dehydrogenase (E2) component of 2-oxoglutarate could be detected indicating that the complex was present, but may be...

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