S. Kim – Aminoacyl-tRNA Synthetases in Biology and Medicine (2014)

Автор: S. Kim
Название книги: Aminoacyl-tRNA Synthetases in Biology and Medicine
Формат: PDF
Жанр: Биологические науки
Страницы: 355
Качество: Изначально компьютерное, E-book

This book will focus on new molecular interactions and novel activities and the associated diseases that have been recently discovered from the studies of eukaryotic and mammalian aminoacyl-tRNA synthetases. In addition, the potential applications of ARS researches in biotechnology and medicine will be addressed.

Ever since the structure of the DNA double helix was unveiled more than 60 years
ago, every step in the central dogma of life has undergone major scientific scrutiny.
As the key components and mechanistic insights into the central dogma have been
elucidated, each discovery has greatly impacted our understanding of the basic
operational principles of living organisms. In the flow from gene to protein,
decoding genetic information with appropriate rate and fidelity is critical to sustaining
the vitality of living organisms. Aminoacyl-tRNA synthetases covalently
attach amino acids to the ends of tRNAs, thereby forming the first bridge between
nucleic acid and protein worlds. The discovery of tRNA synthetase activity Berg
and Ofengand (1958) and Schweet et al. (1958) stimulated major efforts to understand
the common catalytic activities of these enzymes, including the chemical
mechanism of aminoacylation, the architectures of the enzymes and their active
sites, substrate recognition, and molecular evolution and proofreading mechanisms.
These subjects have formed the fundamental basis for tRNA synthetase research for
the last 50 years. In the first three chapters of this volume, Perona, Ibba, Guo, and
Yang et al. discuss the past, present, and future of these issues.
As genomic and structural information on different tRNA synthetases from
diverse species has accumulated, some unique structural features of eukaryotic
tRNA synthetases have been revealed. Relative to their bacterial counterparts,
most eukaryotic enzymes were found to have additional unique domains at their
extremities or even inserted into their conserved catalytic domains. The structural
differences between bacterial and eukaryotic tRNA synthetases distinguished this
family of enzymes from the normal evolutionary differences commonly found in
other protein families. The eukaryote-specific structural features have provided
unique capabilities to form diverse functional protein complexes and have opened
new avenues for research. The functional implications for novel protein–protein
interactions and complexes mediated by eukarytotic tRNA synthetases are
reviewed in the chapter by Han et al.
Sophisticated cell biology studies also revealed a surprising biology for mammalian
tRNA synthetases in extracellular space. Although the presence of several
different tRNA synthetases or their antibodies in blood has been detected in autoimmune patients, these early observations were considered to be the result of
cell necrosis, and the etiology of tRNA synthetases and their autoantibodies in
extracellular locations was not well understood. Recent studies have demonstrated
diverse physiological implications of mammalian tRNA synthetases in the extracellular
milieu, implying that these proteins are likely to result from controlled
secretion processes. The number of examples of secreted tRNA synthetases with
distinct activities has increased in recent years. Although information on their
detailed functions and corresponding receptors is still limited, the emergence of
this new family of extracellular signal mediators that is distinct from the more
typical cytokines and hormones is of great interest. In this volume, the current stateof-
the-art on the secretion and functional implications of human tRNA synthetases
in extracellular space is reviewed by Park et al.
Genetic and biochemical studies have uncovered other unexpected roles of
tRNA synthetases. As these enzymes are essential for protein synthesis and are
thus considered “housekeepers,” the involvement of these enzymes in the expression
of their own or other genes was not well anticipated. Surprisingly, several
different tRNA synthetases regulate gene expression at the levels of transcription,
splicing, and translation via non-catalytic and unique mechanisms. Some recent
findings related to these novel functions are addressed by Fox and Martinis in this
volume. While tRNA synthetases can achieve the regulation of gene expression
primarily through their versatile molecular interactions, some of these enzymes can
also regulate gene expression through the generation of intriguing small molecules,
diadenosine polyphosphates, which are emerging as novel second messengers. This
second catalytic activity and its functional implications are addressed by Razin and
Nechushtan.
The functional diversity of human tRNA synthetases is also associated with
various diseases. For instance, some tRNA synthetases and their autoantibodies are
associated with autoimmune diseases such as polymyositis and dermatomyositis,
and there is even a link to some cancers. In addition, mutations in tRNA synthetases
are strongly implicated in Charcot-Marie-Tooth neuropathy, an inherited disorder
of the peripheral nervous system, although the molecular etiology is not yet clearly
understood. Unlike other housekeeping genes, variation in transcription and copy
numbers of tRNA synthetase genes has been observed in many types of cancer. In
addition, many tRNA synthetases appear to interact with factors that are known to
play critical roles in the process of tumorigenesis. The pathological association of
tRNA synthetases with cancer is relatively new and this emerging topic is addressed
by Kwon et al. in this volume.
Eukaryotes have another set of tRNA synthetases that carry out protein synthesis
in mitochondria. Since mitochondria serve as the power plants of the cell, their
malfunction can lead to critical cellular and organismal defects. Interestingly,
similar to their cytoplasmic counterparts, many mitochondrial tRNA synthetases
are associated with human diseases. In their chapter, Florentz and Sizzler address
the biogenesis of mitochondrial tRNA synthetases, their connections to the mitochondrial
translational machinery and respiratory complexes, and pathological
implications for mitochondrial disorders. Since the aminoacylation reaction is essential for cell viability and proliferation,
the inhibition of the catalytic activities of tRNA synthetases has been explored for
therapeutic purposes. Moreover, specific synthetases and their cognate tRNAs are
packaged into retroviruses including human immunodeficiency virus, and in this
context the tRNAs perform a completely different function related to priming of
reverse transcription. Thus, the novel role of synthetases and tRNAs in retroviruses
and the structural distinction between human and bacterial or fungal tRNA synthetases
have provided a basis for the development of anti-infective agents. The
application of naturally occurring or synthetic compounds that can inhibit the
interactions and catalytic activities of different tRNA synthetases and their potential
use as anti-infective agents are reviewed by Musier-Forsyth et al.
Since aminoacyl-tRNA synthetases define the genetic code, they can be used as
tools to expand or modify the linkage between amino acids and codons that has
naturally evolved. Although reprogramming of the genetic code can be achieved by
engineering the specificity of these enzymes for alternate amino acids or tRNAs, a
totally different approach that exploits catalytic RNAs has also proved to be useful.
An artificially selected ribozyme, named flexizyme, can mediate the covalent
linkage of amino acids to the acceptor ends of tRNAs without substrate discrimination.
Although this RNA surrogate of tRNA synthetase does not yet work in vivo, it
can reprogram the natural genetic code when combined with non-natural amino
acids in an appropriate in vitro translation system. This emerging technology is
introduced in this volume by Suga et al.
Translation of the genetic code is the central process of life involving the largest
number of cellular components, and research in the area of translation typically
generates over 20,000 publications annually. Aminoacyl-tRNA synthetases, central
players in translation, were discovered more than half a century ago, and it has been
assumed that by now all major discoveries related to these enzymes have been
uncovered. However, based on the novel biology, chemistry, and medical relevance
that have recently been unveiled, it is clear that a renaissance of tRNA synthetase
research is underway. During the course of evolution, tRNA synthetases have
adopted signal- or metabolite-sensing and novel molecular interaction capabilities.
Equipped with new functional domains, they behave as “molecular transformers,”
changing their structure and function as needed. In particular, efforts to understand
the new functions hidden within higher eukaryotic tRNA synthetases are in high
gear. While the annual number of publications on tRNA synthetases has varied only
slightly over the last decades, research articles on human tRNA synthetases have
increased and make up about 50% of the total synthetase-related publications. This
trend is expected to continue and indeed soar in the next decade. In this volume, we
have selected topics that reflect the recent excitement in tRNA synthetases and
emerging research areas.
The name “aminoacyl-tRNA synthetase” was coined by the Paul Berg group in
1958. In this volume, the authors use different abbreviations to indicate aminoacyltRNA
synthetases including “aaRS” and “ARS.” To indicate specific enzymes, the
three-letter or single-letter symbol for an amino acid is followed by RS. For
instance, glycyl-tRNA synthetase is abbreviated as GlyRS or GRS. The genes encoding each tRNA synthetase are usually indicated by the single letter amino acid
code plus ARS. For example, the gene encoding glycyl-tRNA synthetase is indicated
as GARS. To indicate mitochondrial genes, the authors usually append the
number “2” at the end (e.g., GARS2).
The non-canonical activities of eukaryotic tRNA synthetases used to be considered
as the coincidental products of divergent evolution and were believed to be
functionally less significant than their canonical catalytic activities. However, as
more pathophysiological functions and structures of eukaryotic and human
aminoacyl-tRNA synthetases are revealed, it seems increasingly clear that the
non-catalytic regulatory activities of these proteins were systematically acquired
to meet the demand of complex higher eukaryotic systems, rather than by random
chance during evolution. Thus, aminoacyl-tRNA synthetases appear to form a
unique “functionome” working widely throughout diverse cell signaling pathways
to maintain system homeostasis. The functionome of aminoacyl-tRNA synthetases
is distinguished from other known groups of specific protein networks in a few key
respects. First, it is universal with its presence in all locations of cells, including
extracellular space. Second, it is constitutively expressed and present at relatively
high amounts. Third, its localization and function seem to be primarily controlled
by post-translational modification rather than by transcription, although its expression
can also be regulated by the latter. Fourth, it can sense cellular nutrition such as
amino acid levels and energy status to coordinate protein synthesis with other
regulatory processes. Fifth, while all tRNA synthetases work together for protein
synthesis, each one works idiosyncratically and with a distinct mechanism to
maintain system homeostasis. With these characteristics, tRNA synthetases can
respond rapidly to many different types of stimuli and stresses to prevent system
disturbance. In this regard, aminoacyl-tRNA synthetases in higher eukaryotes can
be considered “guardians for system homeostasis.” This volume provides many
perspectives on the new biology, chemistry, and medicine derived from these
fascinating polyfunctional enzymes and I sincerely thank all the authors for their
contributions.