A Guide for Future Therapeutics Based upon the Function of Enzymes and Proteins in Human Pathologic Metabolic Processes

Authors

  • Umesh C. Gupta Emeritus Research Scientist, Agriculture and Agri-Food Canada, Charlottetown Research and Development Centre, 440 University Ave, Charlottetown, PE, C1A 4N6, Canada
  • Subhas C. Gupta Chairman and Professor, The Department of Plastic Surgery, Loma Linda University School of Medicine, Loma Linda, California 92354, USA

DOI:

https://doi.org/10.6000/1929-2279.2017.06.03.2

Keywords:

Mitochondria, metastasis, obesity, caloric restriction, cardiovascular disease.

Abstract

The investigation updates information on enzymes and proteins related to their classification, functions,properties, and role in human pathology. Enzymes are any of a group of complex or conjugated proteins that areproduced by living cells and act as catalysts in specific biochemical reactions. The three types of enzymes, metabolic,digestive and food-based, play key roles in the treatment of all the major sources of morbidity and mortality includingcancer, dementia, diabetes, cardiac disease, and obesity. The ability to accurately target metabolic pathways andpathologic pathways allow adaptations by changing the expression of specific enzymes implicated in the pathogenesis orprevention of diseases. This overview provides a summary to guide the development of enzyme-based therapeutics. Thechanges of expression and activity of lipid metabolising enzymes are directly regulated by oncogenic signals. Hyperactivation of the Poly (ADP-ribose) polymerase [PARP] pathway may be exploited to selectively kill cancer cells. Amyloidbeta (Aβ) peptides play a major role in the pathogenesis of Alzheimer's disease (AD). Sphingolipid metabolites playimportant roles in the regulation of glucose metabolism. In diabetes and insulin resistance, sphingosine kinase 1 (SPK1)is the key enzyme in the sphingolipid metabolic pathway. SPK1 gene therapy may represent a novel approach to woundhealing related to diabetes. Several P450s enzymes modulate important steps in the pathogenesis of ischemic heartdisease (IHD). The homologous sirtuin (Sirt) family of proteins have beneficial effects in metabolism and aging-relateddiseases in mammalian systems. These proteins play an important role in maintaining neuronal health during aging.

References

The American Heritage® Stedman's Medical Dictionary, Copyright © 2002, 2001, 1995. Published by Houghton Mifflin Company. All rights reserved. Available from: http://dictionary.reference.com/browse/enzyme

Medical Dictionary for Health Consumers. © 2007 by Saunders, an imprint of Elsevier, Inc., Available from: http://medical-dictionary.thefreedictionary.com/enzyme

Everything-about-enzymes-and-free-lab.html Everything about Enzymes!! (and a free lab!) 2012/04/ All Custom Graphics & Design © 2013 The 3AM Teacher © 2013 Amy Brown, All Rights Reserved. Available from: http://www.amybrownscience.com/

Enzymes. Posted December 21, 2009 at 10: 15 PM Available from: http://www.enotes.com/homework-help/which-three-general-classification-enzymes-125467. http://leavingbio.net/enzymes.htm

Ako H, Nip WK. Enzyme classification and nomenclature. In: Y H Hui Editor. Food Biochemistry and Food processing, Blackwell publishing 2006 Chapter 6, p, 135-154. https://doi.org/10.1002/9780470277577.ch6

Available from: http://en.wikibookps.org/wiki/Biochemistr. https://ca.answers.yahoo.com/question/index?qid=20090301041152AA5iPKW. This page was last modified on 2 February 2014.

The Properties of Enzymes. Resources for Schools. Association of the British Pharmaceutical Industry, ABPI 2015.London, UK. Page 4 of 8. Available from: http://www.abpischools.org.uk/page/modules/enzymes/enzymes4.cfm?coSiteNavigation_allTopic=1), (http://www.abpischools.org.uk/page/modules/enzymes/enzymes4.cfm

Coller HA. Is cancer a metabolic disease? 9582978472. Am J Pathol 2014; 184 (1): 4-17. https://doi.org/10.1016/j.ajpath.2013.07.035

Canadian Cancer Society’s Advisory Committee on Cancer Statistics, Canadian Cancer Statistics 2015, Toronto, ON (May 2015, adapted June 2015), ISSN 0835-2976.

Singh SP, Konwar BK. Virtual screening and molecular descriptor analysis on dietary phytochemicals against heat shock protein 90 enzyme. Lett Drug Des Discov 2014; 11 (1): 40-9. https://doi.org/10.2174/15701808113109990044

Ishaq M, Evans M, Ostrikov K. Effect of atmospheric gas plasmas on cancer cell signaling. Intern J Cancer 2014; 134(7): 1517-28. https://doi.org/10.1002/ijc.28323

Zhang M, Chai YD, Brumbaugh J, Liu X, Rabii R, Feng S, et al. Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes. BMC Cancer 2014; 14 (1). Document No. 223.

Lesche R, Kettschau G, Gromov AV, Böhnke N, Borkowski S, Mönning C, et al. Preclinical evaluation of BAY 1075553, anovel 18F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer. Eur J Nucl Med Mol Imaging 2014; 41(1): 89-101. https://doi.org/10.1007/s00259-013-2527-3

Lettieri BD, Vegliante R, Desideri E, Ciriolo MR. Managing lipid metabolism in proliferating cells: New perspective for metformin usage in cancer therapy. Biochim Biophys Acta Rev Cancer 2014; 1845(2): 317-24. https://doi.org/10.1016/j.bbcan.2014.02.003

Gabitova L, Gorin A, Astsaturov I. Molecular pathways: Sterols and receptor signaling in cancer. Clin Cancer Res 2014; 20 (1): 28-34. https://doi.org/10.1158/1078-0432.CCR-13-0122

Keller KZ, Doctor Z, Dwyer Z, Lee YS. SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mole Cell 2014; 53(5): 700-09. https://doi.org/10.1016/j.molcel.2014.02.015

Merdad A, Karim S, Schulten HJ, Dallol A, Buhmeida A, Al-Thubaity F,et al. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis. Anticancer Res 2014; 34(3): 1355-66.

Winck FV, Belloni M, Pauletti BA, Zanella JDL, Domingues RR, Sherman NE, et al. Phosphoproteome analysis reveals differences in phosphosite profiles between tumorigenic and non-tumorigenic epithelial cells. J Proteomics 2014; 96: 67-81. https://doi.org/10.1016/j.jprot.2013.10.039

Kavanagh ME, O'Sullivan KE, O'Hanlon C, O'Sullivan JN, Lysaght JJ, Reynolds JV. The esophagitis to adenocarcinoma sequence; the role of inflammation. Cancer Lett 2014; 345 (2): 182-9. https://doi.org/10.1016/j.canlet.2013.08.017

Batsaikhan BE, Kurita N, Iwata T, Sato H, Yoshikawa K, Takasu C,et al. The role of activation-induced cytidine deaminase expression in gastric adenocarcinoma. Anticancer Res 2014; 34(2): 995-1000.

Bansal S, Berk M, Alkhouri N, Partrick DA, Fung JJ, Feldstein A. Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma. J Surgical Res 2014; 186(1): 29-38. https://doi.org/10.1016/j.jss.2013.07.001

Nathanson DA, Armijo AL, Tom M, Li Z, Dimitrova E, Austin WR, et al. Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication. J Exp Med 2014; 211 (3): 473-86. https://doi.org/10.1084/jem.20131738

Austin WR, Armijo AL, Campbell DO, Singh AS, Hsieh T, Nathanson D, et al. Nucleoside salvage pathway kinases regulate 39 hematopoiesis by linking nucleotide metabolism with replication stress. J Exp Med 2012; 209(12): 2215-28. https://doi.org/10.1084/jem.20121061

Ren S, Ning Y. Sulfation of 25-hydroxycholesterol regulates lipid metabolism, inflammatory responses, and cell proliferation. Am J Physiol - Endocrinol Metab 2014; 306(2): E123-E130. https://doi.org/10.1152/ajpendo.00552.2013

Wang JS, Rousseaux S, Khochbin S. Sustaining cancer through addictive ectopic gene activation. Curr Opin Oncol 2014; 26(1): 73-7.https://doi.org/10.1097/CCO.0000000000000032

Marin JJG, Monte MJ, Blazquez AG, MacIas RI, Serrano MA, Briz O. The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy. Acta Pharmacol Sin 2014; 35 (1): 1-10. https://doi.org/10.1038/aps.2013.131

Li W, Liu J, Zhao Y. PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells. Mol Carcinogenesis 2014; 53 (5): 403-12. https://doi.org/10.1002/mc.21988

Touil Y, Igoudjil W, Corvaisier M, Dessein AF, Vandomme J, Monte D, et al. Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis. Clin Cancer Res 2014; 20(4): 837-46.https://doi.org/10.1158/1078-0432.CCR-13-1854

Morales JC, Li L, Fattah FJ, Dong Y, Bey EA, Patel M, et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Critical Rev Eukaryotic Gene Expression 2014; 24(1): 15-28.https://doi.org/10.1615/CritRevEukaryotGeneExpr.2013006875

Sugiyama A, Sun J. Immunochemical detection of lipid hydroperoxide- and aldehyde-modified proteins in diseases. Sub-cellular Biochem 2014; 77: 115-25. https://doi.org/10.1007/978-94-007-7920-4_10

Giannopoulos PF, Joshi YB, Praticò D. Novel lipid signaling pathways in Alzheimer's disease pathogenesis. Biochem Pharmacol 2014; 88 (4): 560-4. https://doi.org/10.1016/j.bcp.2013.11.005

Park H, Yoo JS, Kim JY, Hwang BY, Han JS, Yeon SW, et al. Anti-amyloidogenic effects of ID1201, the ethanolic extract of the fruits of Meliatoosendan, through activation of the phosphatidylinositol 3-kinase/Akt pathway. Environ Toxicol Pharmacol 2014; 37(2): 513-20. https://doi.org/10.1016/j.etap.2014.01.008

Gan X, Huang S, Wu L, Wang Y, Hu G, Li G, et al. Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell. Biochim Biophys Acta- Mol Basis Dis 2014; 1842 (2): 220-31. https://doi.org/10.1016/j.bbadis.2013.11.009

Yuyama K, Mitsutake S, Igarashi Y. Pathological roles of ceramide and its metabolites in metabolic syndrome and Alzheimer's disease. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1841 (5): 793-8. https://doi.org/10.1016/j.bbalip.2013.08.002

Jones GRN. The Alzheimer pandemic: Is paracetamol to blame? Inflammation and Allergy - Drug Tar 2014; 13(1): 2-14.

Walsh P, Elsabbagh M, Bolton P, Singh I. Science and society: In search of biomarkers for autism: scientific, social and ethical challenges. 2011; 12: 603-12. https://doi.org/10.1038/nrm3113

Nguyen M, Roth A, Kyzar EJ, Poudel MK, Wong K, StewartAM, et al. Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD). Neurochem Int 2014; 66(1): 15-26. https://doi.org/10.1016/j.neuint.2014.01.002

Blennow K, Hampel H, Zetterberg H. Biomarkers in amyloid-βimmunotherapy trials in Alzheimer's disease. Neuropsychopharm 2014; 39(1): 189-201. https://doi.org/10.1038/npp.2013.154

Petras M, Tatarkova Z, Kovalska M, Mokra D, Dobrota D, Lehotsky J, et al. Hyperhomocysteinemiaas a risk factor for the neuronal system disorders. J Physiol Pharmacol 2014; 65(1): 15-23.

Braidy N, Gai WP, Xu YH, Sachdev P, Guillemin GJ, Jiang XM, et al. Alpha-synuclein transmission and mitochondrialtoxicity in primary human foetal enteric neurons in vitro. Neurotox Res 2014; 25 (2): 170-82. https://doi.org/10.1007/s12640-013-9420-5

Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, et al. Effect of resveratrol on mitochondrial function: Implications in parkin-associated familiar Parkinson's disease. Biochim Biophys Acta Mol Basis Dis 2014; 1842(7): 902-15. https://doi.org/10.1016/j.bbadis.2014.02.010

Yu H, Yuan L, Xu M, Zhang Z, Duan H. Sphingosine kinase 1 improves cutaneous wound healing in diabetic rats. Injury. 2014; 45(7):1054-8.https://doi.org/10.1016/j.injury.2014.03.003

Du Y, Zhang H, Montano S, Hegestam J, Ekberg NR, Holmgren A, et al. Plasma glutaredoxin activity in healthy subjects and patients with abnormal glucose levels or overt type 2 diabetes. Acta Diabetol 2014; 51(2): 225-32. https://doi.org/10.1007/s00592-013-0498-2

Nin V, Chini CCS, Escande C, Capellini V, Chini EN. Deleted in breast cancer 1 (DBC1) protein regulates hepatic gluconeogenesis. J Biol Chem 2014; 289(9): 5518-27. https://doi.org/10.1074/jbc.M113.512913

Hernández C, Garcia-Ramírez M, García-Rocha M, Saez-López C, Valverde AM, Guinovart J, et al. Glycogen storage in the human retinal pigment epithelium: a comparative study of diabetic and non-diabetic donors. Acta Diabetologica 2014; 51(4): 543-52.https://doi.org/10.1007/s00592-013-0549-8

Guo S. Insulin signaling, resistance, and metabolic syndrome: Insights from mouse models into disease mechanisms. J Endocrinol 2014; 220 (2): T1-T23. https://doi.org/10.1530/JOE-13-0327

Salem ESB, Grobe N, Elased KM. Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice. Am J Physiol-Renal Physiol 2014; 306(6): F629-F39. https://doi.org/10.1152/ajprenal.00516.2013

Sun W, Wang Y, Miao X, Wang Y, Zhang L, Xin Y, et alRenal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2. Free Radic Biol Med 2014; 68: 22-34. https://doi.org/10.1016/j.freeradbiomed.2013.11.015

Rowland A, Mangon AA. Cytochrome P450 and ischemic heart disease: Current concepts and future directions. Exp Opin Drug Metab Toxicol 2014; 10(2): 191-213.https://doi.org/10.1517/17425255.2014.859675

Santos CXC, Nabeebaccus AA, Shah AM, Camargo LL, Filho SV, Lopes LR. Endoplasmic reticulum stress and nox-mediated reactive oxygen species signaling in the peripheral vasculature: Potential role in hypertension. Antioxid Redox Signal 2014; 20(1): 121-34. https://doi.org/10.1089/ars.2013.5262

Pillai VB, Sundaresan NR, Gupta MP. Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging. Circ Res 2014; 114 (2): 368-78. https://doi.org/10.1161/CIRCRESAHA.113.300536

Xu SS, Alam S, Margariti A. Epigenetics in vascular disease -Therapeutic potential of new agents. Curr Vasc Pharmacol 2014; 12(1): 77-86.https://doi.org/10.2174/157016111201140327155551

Qin L, Yang YB, Yang YX, Zhu N, Li SX, Liao DF, et al. Anti-inflammatory activity of ezetimibe by regulating NF-κB/MAPK pathway in THP-1 macrophages. Pharmacol 2014; 93(1-2): 69-75. https://doi.org/10.1159/000357953

Brown AJ, Ikonen E, Olkkonen VM. Cholesterol precursors: More than mere markers of biosynthesis. Curr Opin Lipidol 2014; 25(2): 133-9.https://doi.org/10.1097/MOL.0000000000000038

Holven KB, Narverud I, Lindvig HW, Halvorsen B, Langslet G, Nenseter MS, et al. Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment. Atherosclerosis 2014; 233(2): 561-7. https://doi.org/10.1016/j.atherosclerosis.2014.01.022

Sharkey-Toppen TP, Tewari AK, Raman SV. Iron and Atherosclerosis: Nailing Down a Novel Target with Magnetic Resonance. J Cardiovasc Transl Res 2014; 7(5): 533-42. https://doi.org/10.1007/s12265-014-9551-y

Mahmud HM. Fabry's disease-a comprehensive review on pathogenesis, diagnosis and treatment. J Pak Med Assoc 2014; 64(2): 189-94.

Zhu Y, Wang F, Li Q, Zhu M, Du A, Tang W, et al. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos 2014; 42(2): 245-9.https://doi.org/10.1124/dmd.113.055400

Hu M, Tomlinson B. Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin. Exp Opin Drug Metabol Toxicol 2014; 10(1): 51-65. https://doi.org/10.1517/17425255.2014.851667

Nakamura K, Fuster JJ, Walsh K. Adipokines: A link between obesity and cardiovascular disease. J Cardiol 2014; 63(4): 250-9. https://doi.org/10.1016/j.jjcc.2013.11.006

Thewissen MM, Van de Gaar J, Den Boer AT, Munsters MJ, Blaak EE, Duijvestijn A. Monocytes, but not T cells, respond to insulin with Akt (S473) phosphorylation independent of the donor glucometabolic state. Diabetes/Metabol Res Rev 2014; 30(4): 323-32. https://doi.org/10.1002/dmrr.2498

Hebbard L, Ranscht B. Multifaceted roles of Adiponectin in cancer. Best Practice and Research: Clin Endocrinol Metabol 2014; 28(1): 59-69. https://doi.org/10.1016/j.beem.2013.11.005

Gray B, Steyn F, Davies PSW, Vitetta L. Liver function parameters, cholesterol, and phospholipid α linoleic acid are associated with adipokine levels in overweight and obese adults. Nutr Res 2014; 345: 375-82. https://doi.org/10.1016/j.nutres.2014.04.001

Brachmann CB, Sherman JM, Devine SE, Cameron EE,Pillus L, Boeke JD. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 1995; 9(23): 2888-902.https://doi.org/10.1101/gad.9.23.2888

Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 2003; 423(6936): 181-5.https://doi.org/10.1038/nature01578

Abdellatif M. Sirtuins and pyridine nucleotides. Circ Res 2012; 111(5): 642-56.https://doi.org/10.1161/CIRCRESAHA.111.246546

Bolhassani A, Khavari A, Bathaie SZ. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochim Biophys Acta Rev Cancer 2014; 1845 (1): 20-30. https://doi.org/10.1016/j.bbcan.2013.11.001

Deb S, Chin MY, Adomat H, Guns EST. Ginsenoside-mediated blockade of 1α,25-dihydroxyvitamin D3 inactivation in human liver and intestine in vitro. J Steroid Biochem Mol Biol 2014; 141: 94-103. https://doi.org/10.1016/j.jsbmb.2014.01.007

Shao Z, Fu Z, Stahl A, Joyal JS, Hatton C, Juan Aet al. Cytochrome P450 2C8 ω3-long-chain polyunsaturated fatty acid metabolites increase mouse retinal pathologic neovascularization-brief report. Arterioscler Thromb Vasc Biol 2014; 34 (3): 581-6. https://doi.org/10.1161/ATVBAHA.113.302927

Bing Y, Zhu S, Jiang K, Dong G, Li J, Yang Z,et al. Reduction of thyroid hormones triggers down-regulation of hepatic CYP2B through nuclear receptors CAR and TR in a rat model of acute stroke. Biochem Pharmacol 2014; 87(4): 636-49. https://doi.org/10.1016/j.bcp.2013.12.011

Herskovits AZ, Guarente L. SIRT1 in Neurodevelopment and Brain Senescence. Neuron 2014; 81 (3): 471-83. https://doi.org/10.1016/j.neuron.2014.01.028

Shetty A, Hanson R, Korsten P, Shawagfeh M, Arami S, Volkov S,et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther 2014; 8: 349-64.

Yang Y, Zhang Z, Li S, Ye X, Li X, He K. Synergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basis. Fitoterapia 2014; 92: 133-47.https://doi.org/10.1016/j.fitote.2013.10.010

Downloads

Published

2017-08-12

How to Cite

Gupta, U. C. ., & Gupta, S. C. . (2017). A Guide for Future Therapeutics Based upon the Function of Enzymes and Proteins in Human Pathologic Metabolic Processes. Journal of Cancer Research Updates, 6(3), 56–69. https://doi.org/10.6000/1929-2279.2017.06.03.2

Issue

Section

Articles