Metabolite biomarker discovery for metabolic diseases by flux analysis

Metabolites can serve as biomarkers and their identification has significant importance in the study of biochemical reaction and signalling networks. Incorporating metabolic and gene expression data to reveal biochemical networks is a considerable challenge, which attracts a lot of attention in recent research. In this paper, we propose a promising approach to identify metabolic biomarkers through integrating available biomedical data and disease-specific gene expression data. A Linear Programming (LP) based method is then utilized to determine flux variability intervals, therefore enabling the analysis of significant metabolic reactions. A statistical approach is also presented to uncover these metabolites. The identified metabolites are then verified by comparing with the results in the existing literature. The proposed approach here can also be applied to the discovery of potential novel biomarkers.

[1]  R. Goodacre,et al.  Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis , 2003, Springer US.

[2]  Yin Zhang,et al.  Solving large-scale linear programs by interior-point methods under the Matlab ∗ Environment † , 1998 .

[3]  B. Palsson The challenges of in silico biology , 2000, Nature Biotechnology.

[4]  D. Bonthron,et al.  Both isoforms of ketohexokinase are dispensable for normal growth and development. , 2010, Physiological genomics.

[5]  D. Ramkrishna,et al.  Metabolic Engineering from a Cybernetic Perspective. 1. Theoretical Preliminaries , 1999, Biotechnology progress.

[6]  B. Åsling,et al.  4-Aminobutyrate Aminotransferase (ABAT): Genetic and Pharmacological Evidence for an Involvement in Gastro Esophageal Reflux Disease , 2011, PloS one.

[7]  Thomas D. Giles,et al.  Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[8]  R. Webb,et al.  The Role of Uridine Adenosine Tetraphosphate in the Vascular System , 2011, Advances in Pharmacological Sciences.

[9]  Sanjay Ranka,et al.  An Iterative Algorithm for Metabolic Network-Based Drug Target Identification , 2006, Pacific Symposium on Biocomputing.

[10]  Masayoshi Takeuchi,et al.  Pyridoxamine, an inhibitor of advanced glycation end product (AGE) formation ameliorates insulin resistance in obese, type 2 diabetic mice. , 2010, Protein and peptide letters.

[11]  Xiaobo Zhou,et al.  Predicting enzyme targets for cancer drugs by profiling human Metabolic reactions in NCI-60 cell lines , 2010, BMC Bioinformatics.

[12]  C. Warden,et al.  A novel mouse Chromosome 2 congenic strain with obesity phenotypes , 2004, Mammalian Genome.

[13]  J. Reich,et al.  Energy metabolism of the cell : a theoretical treatise , 1981 .

[14]  Albert-László Barabási,et al.  The Activity Reaction Core and Plasticity of Metabolic Networks , 2005, PLoS Comput. Biol..

[15]  C. Langefeld,et al.  Peroxisome Proliferator‐activated Receptor γ 2 and Acyl‐CoA Synthetase 5 Polymorphisms Influence Diet Response , 2007, Obesity.

[16]  I. Goryanin,et al.  Human metabolic network reconstruction and its impact on drug discovery and development. , 2008, Drug discovery today.

[17]  N. Bhagavan,et al.  Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways , 2002 .

[18]  Paul Poirier,et al.  Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss: An Update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease From the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism , 2006, Circulation.

[19]  Bin Song,et al.  Mining Metabolic Networks for Optimal Drug Targets , 2007, Pacific Symposium on Biocomputing.

[20]  Markus J. Herrgård,et al.  Network-based prediction of human tissue-specific metabolism , 2008, Nature Biotechnology.

[21]  Monica L. Mo,et al.  Global reconstruction of the human metabolic network based on genomic and bibliomic data , 2007, Proceedings of the National Academy of Sciences.

[22]  G. Bell,et al.  Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration , 2012, Diabetologia.

[23]  Kenneth J. Kauffman,et al.  Advances in flux balance analysis. , 2003, Current opinion in biotechnology.

[24]  S. Yamagishi,et al.  Pyridoxamine, an Inhibitor of Advanced Glycation End Product (AGE) Formation Ameliorates Insulin Resistance in Obese, Type 2 Diabetic Mice , 2010 .

[25]  D. Fell Understanding the Control of Metabolism , 1996 .

[26]  H. Öhlin,et al.  Aldehyde Dehydrogenase Activity and Large Vessel Disease in Diabetes Mellitus: A Preliminary Study , 1986, Diabetes.

[27]  R. Codario Type 2 Diabetes, Pre-Diabetes, and the Metabolic Syndrome , 2005 .

[28]  M. Hayden,et al.  Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  R. Mahadevan,et al.  The effects of alternate optimal solutions in constraint-based genome-scale metabolic models. , 2003, Metabolic engineering.

[30]  M. Andrades,et al.  Glycolaldehyde Induces Oxidative Stress in the Heart: A Clue to Diabetic Cardiomyopathy? , 2010, Cardiovascular Toxicology.

[31]  Yasuhiro Nakamura,et al.  The farnesoid X receptor regulates transcription of 3β-hydroxysteroid dehydrogenase type 2 in human adrenal cells , 2009, Molecular and Cellular Endocrinology.

[32]  Thomas D. Giles,et al.  Council on Nutrition, Physical Activity, and Metabolism Statement on Obesity and Heart Disease From the Obesity Committee of the Weight Loss: An Update of the 1997 American Heart Association Scientific Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of , 2006 .

[33]  J. Bailey Complex biology with no parameters , 2001, Nature Biotechnology.

[34]  E. Ruppin,et al.  Predicting metabolic biomarkers of human inborn errors of metabolism , 2009, Molecular systems biology.

[35]  J. Dent,et al.  Epidemiology of gastro-oesophageal reflux disease: a systematic review , 2005, Gut.

[36]  I. Grossmann,et al.  Recursive MILP model for finding all the alternate optima in LP models for metabolic networks , 2000 .