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## IntechOpen Book Series Biochemistry Volume 18

Xianquan Zhan received his M.D. and Ph.D. training in preventive medicine at the West China University of Medical Sciences from 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics at the Central South University and University of Tennessee Health Science Center (UTHSC). He worked at UTHSC and Cleveland Clinic in USA from 2001 to 2012, and achieved the rank of Associate Professor at UTHSC. After that, he

became a Full Professor at the Central South University and Shandong First Medical University, and an Advisor of MS/PhD graduate students and postdoctoral fellows. He is also a Fellow of the Royal Society of Medicine, Fellow of EPMA, European EPMA National Representative, full member of the American Society of Clinical Oncology (ASCO), member of the American Association for the Advancement of Sciences (AAAS), Editor-In-Chief of the International Journal of Chronic Diseases & Therapy, Associate Editor of the EPMA Journal and BMC Medical Genomics, and Guest Editor of Frontiers in Endocrinology and Mass Spectrometry Reviews. He has published more than 130 articles, 23 book chapters, 4 books, and 2 US patents in the field of clinical proteomics and biomarkers.

### **Editor of Volume 18: Xianquan Zhan**

University Creative Research Initiatives Center Shandong First Medical University

**Book Series Editor: Miroslav Blumenberg** NYU Langone Medical Center, New York, USA

## Scope of the Series

Biochemistry, the study of chemical transformations occurring within living organisms, impacts all of life sciences, from molecular crystallography and genetics, to ecology, medicine and population biology. Biochemistry studies macromolecules proteins, nucleic acids, carbohydrates and lipids –their building blocks, structures, functions and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins and hormones, which play roles in the life process. Biochemical experimentation, besides coopting the methods of classical chemistry, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron

microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation etc. More recently, biochemistry embraced the 'big data' omics systems.

Contents

*by Noriyuki Murai*

**Preface XI**

**Chapter 1 1**

**Chapter 2 25**

**Chapter 3 39**

**Chapter 4 55**

**Chapter 5 77**

**Chapter 6 95**

Branching and Mixing: New Signals of the Ubiquitin Signaling System *by Daniel Perez-Hernandez, Marta L. Mendes and Gunnar Dittmar*

Ubiquitin-Independent Proteasomal Degradation Mediated by Antizyme

Lys63-Linked Polyubiquitination of Transforming Growth Factor β Type I

Ubiquitination and Deubiquitination in Melanoma Research and

New Discoveries on the Roles of "Other" HECT E3 Ubiquitin Ligases

Abnormal Ubiquitination of Ubiquitin-Proteasome System in Lung

Receptor (TβRI) Specifies Oncogenic Signaling

*by Jie Song and Maréne Landström*

Clinically Relevant Outcomes *by Jia Guo and Jianglin Guo*

in Disease Development

Squamous Cell Carcinomas

*by Emma I. Kane and Donald E. Spratt*

*by Xianquan Zhan and Miaolong Lu*

Initial biochemical studies have been exclusively analytic: dissecting, purifying and examining individual components of a biological system; in exemplary words of Efraim Racker, (1913 - 1991) "Don't waste clean thinking on dirty enzymes." Today however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe fully a particular biological system. The "big data" metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the proteins comprising e.g., serum; metagenomics can identify all the genes in a complex environment e.g., bovine rumen. This Biochemistry Series will address both the current research on biomolecules, and the emerging trends with great promise.

## Contents


Preface

The ubiquitin-proteasome pathway consists of ubiquitin, substrate proteins, E1 enzymes, E2 enzymes, E3 enzymes, and proteasome. Ubiquitin is a highly conserved small protein with 76 amino acids and about 8.5 kDa. E1 enzymes are ubiquitin-activating enzymes. E2 enzymes are ubiquitin-conjugating enzymes. E3 enzymes are ubiquitin-ligases. Proteasome is a 26S complex, an organelle in the cell, which contains one 20S core and two 19S lids. The ubiquitin-proteasome pathway consists of a series of enzymatic reactions: E1 binds ubiquitin to activate ubiquitin in ATP-dependent fashion, the activated ubiquitin is conjugated with E2, and then ubiquitin-conjugated E2 in concert with E3 ligases recognizes substrate proteins and chemically covalently attaches ubiquitin (monomer or polyubiquitin chain) to substrate proteins (ubiquitinated proteins). The ubiquitinated proteins are delivered to the proteasome for degradation into peptides and amino acids to be used for synthesis of new proteins. Here, substrate proteins include surplus proteins and misfolded proteins in a cell or tissue. Also, there are the deubiquitinating enzymes that can remove the attached ubiquitin chain. Thus, ubiquitination/deubiquitination is a reverse process in cells. The ubiquitin-proteasome pathway plays crucial roles in degrading most intracellular proteins, and maintaining the balance between protein synthesis and degradation. The changes of components in the ubiquitin-proteasome pathway are associated with multiple pathophysiological processes, such as cancers, and neurodegenerative diseases. For example, the mutated or overexpressed E3 ligases can act as oncogenes, and also some E3 ligases and deubiquitinating enzymes are tumor suppressors. Moreover, the ubiquitin-proteasome pathway is involved in multiple biological processes, including DNA repair, mitophagy, angiogenesis, RTK signaling, NF-kB signaling, and mitochondrial maintenance, which are dynamically regulated by ubiquitination. Also, it is involved in synaptic functions to regulate the

This book focuses on the changes of the components of the ubiquitin-proteasome pathway, the methodology to study the ubiquitin-proteasome pathway, protein ubiquitination, and application of the ubiquitin-proteasome pathway in different diseases. Chapter 1 addresses the branching and mixing – new signals of the ubiquitin signaling system in the following aspects: the ubiquitin-conjugating system, different ubiquitin-like modifications, ubiquitin-chain topology

(homotypic chains, heterotypic chains, and ubl-ubiquitin chains), and detection methods of ubiquitinated targets and chains including biochemical and genetic methods, mass spectrometry-based methods, ubiquitin topology analysis, and detection of branched chains. Chapter 2 addresses the ubiquitin-independent proteasomal degradation mediated by antizyme, which enriched the concept and content of the ubiquitin-proteasome pathway: ubiquitin-dependent proteasomal degradation through ubiquitination, and ubiquitin-independent proteasomal degradation through antizyme. Chapter 3 addresses lys63-linked polyubiquitination of transforming growth factor beta type I receptor (TBRI) specifies oncogenic signaling, and the regulation of its associated signaling pathways. Chapter 4 addresses ubiquitination and deubiquitination, and their potential clinical application value in melanoma. Chapter 5 addresses the new discoveries of more members (AREL1, HACE1, HECTD1, HECTD4, G2E3, and TRIP12) of the HECT E3

functions of the nervous system.
