Cellular Osmolytes: From Chaperoning Protein Folding to Clinical Perspectives

Preface
Contents
Editors and Contributors
About the Editors
Contributors
1: Protein Folding Pathways in the Presence of Osmolytes
	1.1	 Introduction
	1.2	 Biochemical Equilibrium: Unravelling the Stability Ballet of Proteins
	1.3	 Osmolytes
		1.3.1	 Classification of Osmolytes
		1.3.2	 Osmolytes and Their Interaction with Water
	1.4	 Theories of Protein Stabilization by Osmolytes
		1.4.1	 Preferential Hydration Theory
		1.4.2	 Preferential Exclusion Theory
		1.4.3	 Water Replacement Theory
		1.4.4	 Vitrification (Glass Dynamics Hypothesis)
		1.4.5	 Osmophobic Effect
	1.5	 Studies with Some Model Proteins
	1.6	 Summary
	References
2: Effect of Organic Osmolytes on Protein Folding Intermediates
	2.1	 Introduction
	2.2	 Influence of Osmolytes During the Formation of MG State
	2.3	 Osmolytes Induce the Formation of Compact Native State
	2.4	 Osmolytes Induce Folding of Intrinsically Disordered Proteins
	2.5	 Organic Osmolytes Can Modulate Protein Folding Pathways
	2.6	 Modulation of Protein Folding Kinetics by Osmolytes
	2.7	 Osmolytes Induce the Folding of Non-functional Mutant Proteins into Functionally Active Conformations
	2.8	 Summary
	References
3: Role of TMAO on Folding Behavior of Various Proteins Associated with Neurodegeneration
	3.1	 Introduction
	3.2	 Neurodegeneration Is Caused by the Formation of Toxic Protein Inclusions
	3.3	 TMAO Is an Effective Protein Folding-Inducing Agent
	3.4	 Folding Behavior of Various Brain Proteins in the Presence of TMAO
		3.4.1	 Alzheimer’s Disease (AD)
		3.4.2	 Parkinson’s Disease (PD)
		3.4.3	 Dementia
		3.4.4	 Transmissible Spongiform Encephalopathies
		3.4.5	 Huntington’s Disease (HD)
		3.4.6	 Spinocerebellar Ataxia (SCA)
	3.5	 Summary
	References
4: Osmolyte-Mediated Protein Stabilization: Unraveling Interactions Across Conformational Landscapes
	4.1	 Introduction
	4.2	 Protein Folding
		4.2.1	 Protein Folding Models
			4.2.1.1	 Framework Model
			4.2.1.2	 Hydrophobic Collapse Model
			4.2.1.3	 The Classical Nucleation Model
			4.2.1.4	 Folding Funnel Model
		4.2.2	 Native State
		4.2.3	 Protein Folding Intermediates
		4.2.4	 Denatured States
		4.2.5	 Protein Aggregation
	4.3	 Osmolytes
	4.4	 Mechanism of Protein Stabilization by Osmolytes
		4.4.1	 Stabilization of Native State
		4.4.2	 Stabilization of Intermediate State
		4.4.3	 Osmolytes-Induced Folding of Mutant Proteins
	4.5	 Summary
	References
5: Osmolytes as a Promising Therapeutic Strategy for Protein Aggregation Diseases
	5.1	 Introduction
	5.2	 Classification of Osmolytes
	5.3	 Mechanism of Action of Osmolytes
	5.4	 Protein Aggregation
	5.5	 Osmolytes Help to Prevent Protein Aggregation
		5.5.1	 Proline
		5.5.2	 Trimethylamine N-Oxide
		5.5.3	 Trehalose
		5.5.4	 Glycine
		5.5.5	 Glycerol
	5.6	 Therapeutic Potential of the Osmolytes
	5.7	 Limitations of Osmolytes in Therapeutics
	5.8	 Summary and Future Prospects
	References
6: Involvement of Osmolytes in the Pathophysiology of Various Human Diseases
	6.1	 Introduction
	6.2	 Influence of Osmolytes on Protein Structure, Function and Stability
	6.3	 Influence of Osmolytes on Aggregation Propensity of Proteins
	6.4	 Role of Amino Acids and Amino Acid Derivatives in Different Diseases
	6.5	 Role of Methylamine Osmolytes in Disease Pathologies
	6.6	 Role of Sugar and Polyol Osmolytes in Various Diseases
	6.7	 Summary
	References
7: Role of Osmolytes in Cancer
	7.1	 Introduction
	7.2	 Cancer: An Overview
		7.2.1	 Carcinoma
		7.2.2	 Sarcoma
		7.2.3	 Myeloma
		7.2.4	 Leukemia
		7.2.5	 Lymphoma
	7.3	 Molecular Basis of Cancer
		7.3.1	 Tumor Suppressor Genes (TSG)
		7.3.2	 Proto-Oncogenes
		7.3.3	 Oncogenes in Healing Process
	7.4	 Causes of Cancer
		7.4.1	 Chemical Compounds
		7.4.2	 Radiation
		7.4.3	 Smoking, Tobacco, and Alcoholism
			7.4.3.1	 Oral Cancer
			7.4.3.2	 Laryngeal Cancer
			7.4.3.3	 Esophageal Cancer
			7.4.3.4	 Liver Cancer
		7.4.4	 Virus and Bacteria
			7.4.4.1	 HTLV-1
			7.4.4.2	 HBV and HCV
			7.4.4.3	 EBV and HHV-8
			7.4.4.4	 MCV
	7.5	 Osmolytes in Cancer
		7.5.1	 Altered Levels of Osmolytes in Serum of Cancer Patients
		7.5.2	 Osmolyte in Cancer Cell Proliferation
		7.5.3	 Osmolytes in Cancer Metastasis
		7.5.4	 Role of Osmolytes in Apoptosis of Cancer Cells
	7.6	 Summary
	References
8: Harnessing the Power of Osmolytes for Industrial and Pharmaceutical Applications
	8.1	 Introduction
	8.2	 Characteristics of Osmolytes
	8.3	 Classification of Osmolytes
		8.3.1	 Organic Osmolytes
			8.3.1.1	 Polyols and Sugars
			8.3.1.2	 Cyclitols
			8.3.1.3	 Anionic Polyols
		8.3.2	 Amino Acids
		8.3.3	 Methylamines
		8.3.4	 Methyl Sulfonium
		8.3.5	 Urea
	8.4	 Mechanisms of Actions of Osmolytes
		8.4.1	 Preferential Exclusion of a Compatible Osmolyte in Protein Under Stressful Conditions
	8.5	 Osmolytes in Protein Purification
	8.6	 Protein-Destabilizing Conditions: Shared or Independent Routes
	8.7	 Protein Stabilization
	8.8	 Amino Acids as Excipients
	8.9	 Osmolytes in Drug Formulation
	8.10	 Role of Osmolytes in Vaccine Production
	8.11	 Osmolytes in Vaccine Flocculation
	8.12	 Osmolytes for Preserving Purified Protein
	8.13	 Role of Osmolytes in the Nanoencapsulation in the Drug
	8.14	 Role of Each Class of Osmolyte in the Formulation of Neurological Drugs
	8.15	 Conclusion
	References
9: Diverse Biological Functions of Myo-inositol: A Neuro-Metabolite, Osmoprotectant, and Diagnostic Marker
	9.1	 Introduction
	9.2	 Structure and Isomers of Inositol
	9.3	 Synthesis, Degradation, and Depletion of Myo-inositol
	9.4	 Cellular Import and Export of MI
	9.5	 MI as a Nutritional Supplement
	9.6	 MI as an Osmoprotectant
	9.7	 MI as a Ubiquitous Metabolite
	9.8	 MI as a Disease Biomarker
	9.9	 Role of MI in Clinical Conditions
		9.9.1	 Myo-inositol as an Effective Supplement for Polycystic Ovary Syndrome
		9.9.2	 Association of MI with Cancer
		9.9.3	 MI in Cardiovascular Diseases (CVDs)
		9.9.4	 MI in Respiratory Distress Syndrome and Pulmonary Functions
		9.9.5	 MI in Neurodgenerative Diseases
		9.9.6	 MI in Treatment of Trichotillomania
		9.9.7	 MI in Epilepsy
		9.9.8	 MI in AD
		9.9.9	 MI in Parkinson’s Disease (PD)
		9.9.10	 MI in Huntington’s disease (HD)
		9.9.11	 MI in Multiple Sclerosis
	9.10	 Conclusion and Future Perspective
	References
10: Potential of Osmolytes as Diagnostic Biomarkers in Various Diseases
	10.1	 Introduction
		10.1.1	 Osmolytes and Their Role in Maintaining Cellular Homeostasis
		10.1.2	 Osmolytes Modulate Different Biological Processes and Hence in Diseases
		10.1.3	 Potential of Osmolytes as Diagnostic Biomarkers for Diseases
	10.2	 Conclusion
	References
11: Osmolytes as Stress Sensors in Plants: Acclimatizing Plants Under Stress Conditions
	11.1	 Introduction
	11.2	 Activation of Plant Defense Mechanism Under Abiotic Stress
	11.3	 Abiotic Stress and Osmolyte Accumulation in Plants
	11.4	 Biosynthesis and Accumulation of Osmolytes in Plants
		11.4.1	 Amino Acid Osmolytes
			11.4.1.1	 Proline
		11.4.2	 Methylamines
			11.4.2.1	 Glycine Betaine
			11.4.2.2	 Dimethylsulfoniopropionate (DMSP)
			11.4.2.3	 Trimethylamine-N-oxide (TMAO)
		11.4.3	 Carbohydrates
			11.4.3.1	 Trehalose and Sucrose
		11.4.4	 Polyols
			11.4.4.1	 Sorbitol and Mannitol
		11.4.5	 Polyamines
	11.5	 Engineering Plants for Enhanced Stress Tolerance Through Osmolytes
		11.5.1	 Overexpression of Biosynthetic Genes
		11.5.2	 Engineering Stress-Responsive Promoters
		11.5.3	 Metabolic Engineering for Osmolyte Accumulation
		11.5.4	 Genome Editing for Enhanced Osmolyte Accumulation
	11.6	 Transgenic Plants with Osmolyte Synthesizing Genes
		11.6.1	 Transgenic Plants with Enhanced Synthesis of Proline
		11.6.2	 Transgenic Plants with Enhanced Synthesis of Mannitol
		11.6.3	 Transgenic Plants with Enhanced Synthesis of Trehalose
		11.6.4	 Transgenic Plants with Enhanced Synthesis of Betaine
	11.7	 Conclusion and Future Prospectives
	References