Toward a Science of Metabolic Engineering

Bailey, James E.

doi:10.1126/science.2047876

Cited by 1,063 publications

(537 citation statements)

References 71 publications

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“…13,14 Furthermore, salivary gland cells are physiologically endowed with the ability to produce copious amounts of secretory proteins (albeit for exocrine secretion), and thus may prove to be particularly useful for metabolic engineering. 1 The present report provides a fundamental extension of our initial observations concerning the systemic delivery of transgene products from salivary glands. Specifically, we have demonstrated for the first time that a transgene product (hGH), secreted from salivary glands in an endocrine fashion, has systemic biological efficacy.…”

Section: Introductionmentioning

confidence: 64%

“…Intramuscular injection of AdCMVhGH resulted in the lowest levels of serum hGH of any of the three delivery routes examined here, but levels were still in modest excess of those considered therapeutic in humans. [1][2][3] From a number of studies, it appears that transfer of genes to muscle cells results in fairly stable, long-term expression of transgene products, albeit at modest levels likely due to limited, localized cell transduction. 2,19,20 Following virus administration intravenously, average serum hGH levels were quite high.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] In addition to being inconvenient, such a mode of protein therapeutics is usually not cost-efficient, can result in the administration of various impurities, and may not result in physiologically adequate patterns of protein replacement in blood. Growth hormone deficiency in children is an excellent example of one such condition.…”

Section: Introductionmentioning

confidence: 99%

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Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

Goldsmith

Marmary

et al. 1998

Gene Ther

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We have previously suggested that although salivary were approximately 16 ng/ml and rat insulin-like growth glands function in an exocrine manner they might none the factor-1 was elevated approximately 25%. Moreover, less offer a useful way to deliver therapeutic proteins sysserum chemistry profiles of rats subjected to in vivo gene temically. As a direct functional test of this hypothesis, we transfer displayed alterations in the BUN:creatinine ratio constructed a recombinant adenovirus (AdCMVhGH) and triglyceride levels presumably reflecting the anabolic encoding human growth hormone (hGH) and then studied actions of the hGH. These results provide the first demonthe biological action of hGH produced following transfer of stration of systemic biological action from a transgene prothe hGH gene to rat submandibular glands. At 48 h followduct secreted in an endocrine fashion from the salivary ing infusion of AdCMVhGH into these glands via canglands. nulation of the main excretory duct, serum levels of hGH

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Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

Goldsmith

Marmary

et al. 1998

Gene Ther

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“…The oxygen sensitivity of the N‐terminus, and its role binding to RNA, may play an evolutionarily significant role in regulating Rubisco expression (Cohen et al., 2006; Kapralov & Filatov, 2007; Yosef et al., 2004). Regulation of expression can attenuate acute physiological response to perturbation inside or outside the cell (Bailey, 1991; Berry, Mure, & Yerramsetty, 2016). For these reasons, it is possible that this substitutional enrichment associated with the N‐terminus may reflect an initial adaptive attempt to cope with increasing oxidative stress prior to the GOE.…”

Section: Discussionmentioning

confidence: 99%

Constraining the timing of the Great Oxidation Event within the Rubisco phylogenetic tree

et al. 2017

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Ribulose 1,5‐bisphosphate (RuBP) carboxylase/oxygenase (RuBisCO, or Rubisco) catalyzes a key reaction by which inorganic carbon is converted into organic carbon in the metabolism of many aerobic and anaerobic organisms. Across the broader Rubisco protein family, homologs exhibit diverse biochemical characteristics and metabolic functions, but the evolutionary origins of this diversity are unclear. Evidence of the timing of Rubisco family emergence and diversification of its different forms has been obscured by a meager paleontological record of early Earth biota, their subcellular physiology and metabolic components. Here, we use computational models to reconstruct a Rubisco family phylogenetic tree, ancestral amino acid sequences at branching points on the tree, and protein structures for several key ancestors. Analysis of historic substitutions with respect to their structural locations shows that there were distinct periods of amino acid substitution enrichment above background levels near and within its oxygen‐sensitive active site and subunit interfaces over the divergence between Form III (associated with anoxia) and Form I (associated with oxia) groups in its evolutionary history. One possible interpretation is that these periods of substitutional enrichment are coincident with oxidative stress exerted by the rise of oxygenic photosynthesis in the Precambrian era. Our interpretation implies that the periods of Rubisco substitutional enrichment inferred near the transition from anaerobic Form III to aerobic Form I ancestral sequences predate the acquisition of Rubisco by fully derived cyanobacterial (i.e., dual photosystem‐bearing, oxygen‐evolving) clades. The partitioning of extant lineages at high clade levels within our Rubisco phylogeny indicates that horizontal transfer of Rubisco is a relatively infrequent event. Therefore, it is possible that the mutational enrichment periods between the Form III and Form I common ancestral sequences correspond to the adaptation of key oxygen‐sensitive components of Rubisco prior to, or coincident with, the Great Oxidation Event.

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“…Metabolic fluxes are key descriptors of a cell's physiology (Nielsen, 2003) and targets of metabolic engineering for overproduction (Bailey, 1991). Metabolic flux analysis (MFA) is the gold standard method for the quantification of the fluxes (Stephanopoulos, 1999).…”

Section: Introductionmentioning

confidence: 99%

Identification of optimal measurement sets for complete flux elucidation in metabolic flux analysis experiments

Chang¹,

Suthers²,

Maranas³

2008

Biotech & Bioengineering

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Metabolic flux analysis (MFA) methods use external flux and isotopic measurements to quantify the magnitude of metabolic flows in metabolic networks. A key question in this analysis is choosing a set of measurements that is capable of yielding a unique flux distribution (identifiability). In this article, we introduce an optimization-based framework that uses incidence structure analysis to determine the smallest (or most cost-effective) set of measurements leading to complete flux elucidation. This approach relies on an integer linear programming formulation OptMeas that allows for the measurement of external fluxes and the complete (or partial) enumeration of the isotope forms of metabolites without requiring any of these to be chosen in advance. We subsequently query and refine the measurement sets suggested by OptMeas for identifiability and optimality. OptMeas is first tested on small to medium-size demonstration examples. It is subsequently applied to a large-scale E. coli isotopomer mapping model with more than 17,000 isotopomers. A number of additional measurements are identified leading to maximum flux elucidation in an amorphadiene producing E. coli strain.

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Toward a Science of Metabolic Engineering

Cited by 1,063 publications

References 71 publications

Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

Systemic action of human growth hormone following adenovirus-mediated gene transfer to rat submandibular glands

Constraining the timing of the Great Oxidation Event within the Rubisco phylogenetic tree

Identification of optimal measurement sets for complete flux elucidation in metabolic flux analysis experiments

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