Molecular Strategies of Creatures to Survive in Acidic Environments

196 Pages·2021·1.94 MB·English

by  Hiroshi Kobayashi

Molecular Strategies of
Creatures to Survive in
Acidic Environments

Molecular Strategies of
Creatures to Survive in
Acidic Environments
:
Invitation to the Acidic World
By
Hiroshi Kobayashi
Molecular Strategies of Creatures to Survive in Acidic Environments:
Invitation to the Acidic World

By Hiroshi Kobayashi

This book first published 2021

Cambridge Scholars Publishing

Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK

British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library

Copyright © 2021 by Hiroshi Kobayashi

All rights for this book reserved. No part of this book may be reproduced,
stored in a retrieval system, or transmitted, in any form or by any means,
electronic, mechanical, photocopying, recording or otherwise, without
the prior permission of the copyright owner.

ISBN (10): 1-5275-7023-1
ISBN (13): 978-1-5275-7023-8
CONTENTS

Preface ..................................................................................................... viii

Water structure and pH ............................................................................... 1

Chemiosmotic theory and H+-ATPase ........................................................ 6

Microorganisms in the acidic world ......................................................... 10
1. Bacterial structure ........................................................................... 10
2. Cytoplasmic pH regulation in E. coli .............................................. 12
3. Cytoplasmic pH regulation in Enterococci ..................................... 17
4. Significance of the proton-motive force in microorganisms ........... 25
5. Survival in extremely acidic conditions .......................................... 27
Acid resistance systems ................................................................. 29
6. Different genes are working under acidic conditions ...................... 35
Na+ extrusion systems ................................................................... 36
K+ uptake systems ......................................................................... 37
Energy metabolism at acidic pH values ........................................ 37
Other systems ................................................................................ 38
Gene expression measured by DNA array and RNA sequencing
Techniques ............................................................................... 40
7. Acidophilic bacteria ........................................................................ 42

Mammalian cells in the acidic world ........................................................ 45
1. Blood pH regulation ........................................................................ 45
Blood acidosis ............................................................................... 47
2. Acidification of tissues .................................................................. 50
3. Cytosolic pH regulation in mammalian cells .................................. 51
Na+/H+ exchanger (NHE) ............................................................. 51
Proton-translocating ATPase ......................................................... 53
Bicarbonate transport systems ....................................................... 54
4. Acidification of the interior of organelles ....................................... 55
5. Studies of mammalian cell functions under acidic conditions ........ 58
Preparation of the acidic medium .................................................. 60
Internal pH under acidic conditions .............................................. 61
vi Contents
6. Mammalian enzyme activity increases at acidic pH values ............ 62
G protein-coupled receptors (GPCRs) ........................................... 63
GPR4 ............................................................................................. 63
TDAG8 (T cell death-associated gene 8, GPR65) ........................ 64
OGR1 (ovarian cancer G protein-coupled receptor 1, GPR68) ..... 65
G2A (G protein coupled receptor 132, GPR132) .......................... 66
Physiological significance of pH-sensitive GPCRs ....................... 67
Acid-sensing ion channel (ASIC) ................................................. 67
Signal pathways in immune cells .................................................. 70
Signal pathways for bone homeostasis .......................................... 74
Signal pathways in cancer cells ..................................................... 74
Factors functioning at acidic pH values with neither elevated
expression nor activation ......................................................... 75
7. Gene expression in cancer cells under acidic conditions ................ 76
8. Expression of acidosis-dependent genes in cancer cell nests .......... 80

Theoretical considerations on gene expression and its regulation ............ 86
1. Gene expression in mammalian cells ............................................. 86
The human genome contains regions whose sequence
is random ................................................................................. 87
Regulatory proteins for gene transcription in mammalian cells .... 88
2. Activation of cell surface receptors ................................................. 95
Monte Carlo computer simulation ................................................. 96
Cells contain excess receptors ....................................................... 99
Clustering of receptors on the cell surface .................................. 100
3. Signal pathways from external ligands to initiation of gene
transcription ................................................................................. 104
4. Regulation of signal pathways ...................................................... 107
5. Hypothetical considerations for future experimental
investigation ................................................................................ 111

Anti-cancer drugs ................................................................................... 114
1. Potent targets for acidosis-dependent anti-cancer drugs .............. 116
2. Anti-cancer drugs working preferentially in acidified cancer cell
nests ............................................................................................. 117
Statins and manumycin A ........................................................... 118
Cantharidin, okadaic acid, and endothall ................................... 121
Ionomycin ................................................................................... 122
3. Prospective clinical usage of acidosis-dependent anti-cancer
drugs ............................................................................................ 123
4. Exploitation of other drugs specific to acidic cancer cell nests..... 125
Molecular Strategies of Creatures to Survive in Acidic Environments vii
Conclusion .............................................................................................. 127

Acknowledgements ............................................................................... 129

References .............................................................................................. 130

Index ....................................................................................................... 168
PREFACE

It became generally accepted in the 19th century, perhaps even earlier, that
living organisms were able to synthesize various compounds only when they
were alive—such compounds were called organic compounds. At the end of
the 19th century, Eduard Buchner found that alcohol can be synthesized in
disrupted yeasts, demonstrating that life is not an essential factor for the
production of organic compounds (Kohler 1971). This finding led to the
discovery of enzyme-catalyzed chemical reactions. With this milestone
discovery, a new research field, biochemistry, began, which sought to reveal
the phenomena of living organisms based on chemical reactions. Research
expanded into related areas—molecular biology, molecular genetics, cell
biology—all of which are now considered branches of the life sciences.
The category of living organisms encompasses a huge number of species,
ranging from microscopic viruses to humans. Researchers in the field have
generally assumed that all living organisms have common mechanisms
essential for supporting life and have focused their investigations on the
discovery and analysis of such common mechanisms. Living organisms are
diverse with their habitats covering almost all the areas of the earth. Different
living things live under different conditions of temperature, pH, salinity, and
hydrostatic pressure, etc., leading us to assume that living things have
different systems to help them survive in different environments. It remains a
challenge for researchers to successfully dissect the strategies that organisms
use and the results of their research can help develop our understanding of life
at the individual level.
Molecular Strategies of Creatures to Survive in Acidic Environments ix
It is a common idea that such strategies developed through genetic
alteration over a long time span. There are two main theories. One is that
genetic alteration occurred randomly and species acquired new and useful
systems for survival coincidentally under particular environment conditions,
which were then selected for, and species that failed to develop such systems
became extinct—Darwin’s theory of natural selection. The second theory is
the neutral evolution theory, which proposes that genetic alterations occurred
and accumulated in a certain direction independently of the environmental
conditions (Charlesworth, Barton, and Charlesworth 2017). We have limited
means to know how evolution progressed historically and verification has not
been established experimentally; as such, we have only assumptions based on
the analysis of fossils and genetic variations in present-day organisms.
Genetic alterations may have been accumulated through the above two
evolutional processes and occurred by turns or at the same time, leading to the
evolution of modern organisms.
Living things are also impacted by changes in the conditions of their
surroundings—from the womb to the tomb and through changes in climate
and their travels. They may develop various strategies to overcome
environmental changes. Unlike the evolution of living things, these strategies
can be dissected experimentally. Among the conditions they encounter,
changes in the pH of their habitat can often occur and threaten their continued
existence. The main component of living things is protein, which consists of
amino acids that have both acidic and alkaline residues; protonation and
deprotonation of these residues occur within a narrow pH range. Since all
enzyme activities mediating cellular reactions are pH-dependent, changes in
pH dramatically affect cellular functions, often leading to death. We set
ourselves, therefore, the challenge of trying to shed light on how living things
can overcome changes in pH.