Kinetic Modeling of Metabolic Pathways: Application to Serine Biosynthesis

2013 ◽  
pp. 113-121 ◽  
Author(s):  
Kieran Smallbone ◽  
Natalie J. Stanford
Keyword(s):  
Kinetic Modeling ◽  
Metabolic Pathways ◽  
Serine Biosynthesis

scholarly journals Cysteine catabolism and the serine biosynthesis pathway support pyruvate production during pyruvate kinase knockdown in pancreatic cancer cells

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Lei Yu ◽  
Shao Thing Teoh ◽  
Elliot Ensink ◽  
Martin P. Ogrodzinski ◽  
Che Yang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pyruvate Kinase ◽  
Metabolic Pathways ◽  
Treatment Options ◽  
Ductal Adenocarcinoma ◽  
Metabolic Enzyme ◽  
Biosynthesis Pathway ◽  
Pancreatic Cancer Cells ◽  
Serine Biosynthesis

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Pyruvate kinase, especially the M2 isoform (PKM2), is highly expressed in PDAC cells, but its role in pancreatic cancer remains controversial. To investigate the role of pyruvate kinase in pancreatic cancer, we knocked down PKM2 individually as well as both PKM1 and PKM2 concurrently (PKM1/2) in cell lines derived from a KrasG12D/-; p53-/- pancreatic mouse model. Methods We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine metabolic profiles of wildtype and PKM1/2 knockdown PDAC cells. We further used stable isotope-labeled metabolic precursors and LC-MS/MS to determine metabolic pathways upregulated in PKM1/2 knockdown cells. We then targeted metabolic pathways upregulated in PKM1/2 knockdown cells using CRISPR/Cas9 gene editing technology. Results PDAC cells are able to proliferate and continue to produce pyruvate despite PKM1/2 knockdown. The serine biosynthesis pathway partially contributed to pyruvate production during PKM1/2 knockdown: knockout of phosphoglycerate dehydrogenase in this pathway decreased pyruvate production from glucose. In addition, cysteine catabolism generated ~ 20% of intracellular pyruvate in PDAC cells. Other potential sources of pyruvate include the sialic acid pathway and catabolism of glutamine, serine, tryptophan, and threonine. However, these sources did not provide significant levels of pyruvate in PKM1/2 knockdown cells. Conclusion PKM1/2 knockdown does not impact the proliferation of pancreatic cancer cells. The serine biosynthesis pathway supports conversion of glucose to pyruvate during pyruvate kinase knockdown. However, direct conversion of serine to pyruvate was not observed during PKM1/2 knockdown. Investigating several alternative sources of pyruvate identified cysteine catabolism for pyruvate production during PKM1/2 knockdown. Surprisingly, we find that a large percentage of intracellular pyruvate comes from cysteine. Our results highlight the ability of PDAC cells to adaptively rewire their metabolic pathways during knockdown of a key metabolic enzyme.

Drug Target Selection for Trypanosoma cruzi Metabolism by Metabolic Control Analysis and Kinetic Modeling

2019 ◽  
Vol 26 (36) ◽  
pp. 6652-6671 ◽  
Author(s):  
Emma Saavedra ◽  
Zabdi González-Chávez ◽  
Rafael Moreno-Sánchez ◽  
Paul A.M. Michels
Keyword(s):  
Trypanosoma Cruzi ◽  
Metabolic Control ◽  
Kinetic Modeling ◽  
Metabolic Pathways ◽  
Drug Target ◽  
Metabolic Modeling ◽  
Metabolic Control Analysis ◽  
Control Analysis ◽  
Control Coefficient ◽  
Flux Control

In the search for therapeutic targets in the intermediary metabolism of trypanosomatids the gene essentiality criterion as determined by using knock-out and knock-down genetic strategies is commonly applied. As most of the evaluated enzymes/transporters have turned out to be essential for parasite survival, additional criteria and approaches are clearly required for suitable drug target prioritization. The fundamentals of Metabolic Control Analysis (MCA; an approach in the study of control and regulation of metabolism) and kinetic modeling of metabolic pathways (a bottom-up systems biology approach) allow quantification of the degree of control that each enzyme exerts on the pathway flux (flux control coefficient) and metabolic intermediate concentrations (concentration control coefficient). MCA studies have demonstrated that metabolic pathways usually have two or three enzymes with the highest control of flux; their inhibition has more negative effects on the pathway function than inhibition of enzymes exerting low flux control. Therefore, the enzymes with the highest pathway control are the most convenient targets for therapeutic intervention. In this review, the fundamentals of MCA as well as experimental strategies to determine the flux control coefficients and metabolic modeling are analyzed. MCA and kinetic modeling have been applied to trypanothione metabolism in Trypanosoma cruzi and the model predictions subsequently validated in vivo. The results showed that three out of ten enzyme reactions analyzed in the T. cruzi anti-oxidant metabolism were the most controlling enzymes. Hence, MCA and metabolic modeling allow a further step in target prioritization for drug development against trypanosomatids and other parasites.

Accelerating Metabolic Pathways Simulation using GPUs

2010 ◽  
Author(s):  
Sohan Lal ◽  
Kolin Paul ◽  
James Gomes
Keyword(s):  
Metabolic Pathways

Allene oxidation in jet-stirred reactor : a kinetic modeling study

1990 ◽  
Vol 87 ◽  
pp. 1159-1172 ◽  
Author(s):  
P Dagaut ◽  
M Cathonnet ◽  
B Aboussi ◽  
JC Boettner
Keyword(s):  
Kinetic Modeling ◽  
Stirred Reactor ◽  
Allene Oxidation ◽  
Modeling Study

Mapping metabolic pathways in chemical property space paves the way for new leishmanicidals

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
E Vikeved ◽  
R Buonfiglio ◽  
T Kogej ◽  
A Backlund
Keyword(s):  
Chemical Property ◽  
Metabolic Pathways ◽  
Property Space ◽  
The Way

METABOLISM OF PREGNENOLONE-3-SULPHATE IN THE PERFUSED DOG LIVER

1965 ◽  
Vol 49 (3) ◽  
pp. 427-435 ◽  
Author(s):  
K. D. Voigt ◽  
J. Tamm ◽  
U. Volkwein ◽  
H. Schedewie
Keyword(s):  
Metabolic Pathways ◽  
Dog Liver ◽  
Steroid Conjugates

ABSTRACT Pregnenolone-sulphate (400 mg) was perfused through isolated dog livers. The following steroids were isolated in the perfusate: pregnenolone, progesterone, dehydroepiandrosterone, androst-5-ene-diol and the two steroid conjugates, i. e. pregnenolone-sulphate and dehydroepiandrosterone-sulphate. Two »free« steroids and one steroid conjugate could not be characterized. A tentative scheme for the metabolic pathways of pregnenolone-sulphate is presented.

Estimation and Kinetic Modeling of Human Arm using Wearable Robot Arm

2016 ◽  
Vol 136 (4) ◽  
pp. 254-262 ◽  
Author(s):  
Takahiro Yamazaki ◽  
Sho Sakaino ◽  
Toshiaki Tsuji
Keyword(s):  
Kinetic Modeling ◽  
Robot Arm ◽  
Wearable Robot ◽  
Human Arm
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