Medical Biochemistry

CHAPTER 1

Introduction

John W. Baynes and Marek H. Dominiczak

Biochemistry and clinical medicine

We call this book ‘Medical Biochemistry’ because it focuses on aspects of biochemistry relevant to medicine: on explaining how the body works as a chemical system and how it malfunctions during illness. Biochemistry provides a foundation for understanding the action of new drugs, such as antidepressants, drugs used to treat diabetes, hypertension and heart failure, and those that lower blood lipids. It describes clinical applications of recombinant proteins, viral vectors and the ‘-omics’: proteomics, genomics and metabolomics. By providing insight into nutrition and exercise, and metabolic stress, it contributes to understanding how diet and lifestyle influence our health and performance, as well as how the organism ages. It describes how cellular signaling and communications systems respond to endogenous and environmental stress. It also incorporates enormous progress made in recent years in understanding human genetics, and links it to the emerging fields of nutrigenomics and pharmacogenomics, that will hopefully create a basis for therapies customized to an individual's genetic make-up.

One studies biochemistry to understand the interplay of nutrition, metabolism and genetics in health and disease

The human organism is, on the one hand, a tightly controlled, integrated and self-contained metabolic system. On the other, it is a system that is open and communicates with its environment. Despite these two seemingly contradictory characteristics, the body manages to maintain its internal environment for decades. We regularly top up our fuel (consume food) and water, and take up oxygen from inspired air to use for oxidative metabolism (which is in fact a chain of low-temperature combustion reactions). We then use the energy generated from metabolism to perform work and to maintain body temperature. We get rid of (exhale or excrete) carbon dioxide, water and nitrogenous waste. The amount and quality of food we consume have significant impact on our health – malnutrition on the one hand and obesity and diabetes on the other, are currently major public health issues worldwide.

The entire biochemistry on two pages

It is said that any text can be shortened. Thus, we took a plunge and attempted to condense our book to less than two pages. This is meant to give the reader a general overview and to create a framework for the study of subsequent chapters. The items highlighted below take you through the contents of chapters in this book.

The major structural components of the body are carbohydrates, lipids and proteins

Proteins are building blocks and catalysts; as structural units, they form the ‘architectural’ framework of tissues; as enzymes, together with helper molecules (coenzymes and cofactors), they catalyze biochemical reactions. Lipids, such as cholesterol and phospholipids, form the backbone of biological membranes.

Carbohydrates and lipids as monomers or relatively simple polymers are our major energy sources. They can be stored in tissues as glycogen and triglycerides. However, carbohydrates can also be linked to both proteins and lipids, and form complex structures (glycoconjugates) essential for cell signaling systems and processes such as cell adhesion and immunity.

Chemical variables, such as pHoxygen tension, and inorganic ion and buffer concentrations, define the homeostatic environment in which metabolism takes place. Minute changes in this environment, for example, less than a fifth of a pH unit or just a few degrees' change in body temperature, can be life-threatening.

The blood is a unique transport medium that participates in the exchange of gases, fuels, metabolites – and information – between tissues. Moreover, the plasma, which can be easily sampled and analyzed, is a ‘window’ on metabolism and a rich source of clinical information.

Biological membranes partition metabolic pathways into different cellular compartments. Their water-impermeable structure is dotted with an array of ‘doors and gates’ (membrane transporters) and ‘locks’ that accept a variety of keys (hormone, cytokine and other receptors) and generate intracellular signals. They play a fundamental role in ion and metabolite transport, and in signal transduction both from one cell to another, and within individual cells. The fact that most of the body's energy is consumed to maintain ion and metabolite gradients across membranes emphasizes the importance of these processes. Also, cells throughout the body are critically dependent on membrane potentials for nerve transmission, muscle contraction, nutrient transport and the maintenance of cell volume.

Energy released from nutrients is distributed in the form of adenosine triphosphate

Energy capture in biological systems occurs through oxidative phosphorylation which takes place in the mitochondrion. This process involves oxygen consumption, or respiration, by which the organism uses the energy of fuels to produce a hydrogen ion gradient across the mitochondrial membrane and capture this energy as adenosine triphosphate (ATP). Biochemists call ATP the ‘common currency of metabolism’ because it allows energy from fuel metabolism to be used for work, transport and biosynthesis.

Metabolism is a sophisticated network of chemical processes

Carbohydrates and lipids are our primary sources of energy, but our nutritional requirements also include amino acids (components of proteins), inorganic molecules containing sodium potassium phosphate and other atoms, and micronutrients – vitamins and trace elements. Glucose is metabolized through glycolysis, a universal non-oxygen requiring (anaerobic) pathway for energy production. It yields pyruvate, setting the stage for oxidative metabolism in the mitochondria. It also generates metabolites that are the starting points for synthesis ofamino acidsproteinslipids and nucleic acids.

Glucose is the most important fuel for the brain: therefore maintaining its concentration in plasma is essential for survival. Glucose supply is linked to the metabolism of glycogen, its short-term storage form. Glucose homeostasis is regulated by the hormones that coordinate metabolic activities among cells and organs – primarily insulin and glucagon, and also epinephrine and cortisol.

Oxygen is essential for energy production but can also be toxic

During aerobic metabolism, pyruvate is transformed into acetyl coenzyme A (acetyl-CoA), the common intermediate in the metabolism of carbohydrates, lipids and amino acids. Acetyl-CoA enters the central metabolic engine of the cell, the tricarboxylic acid cycle (TCA cycle) located in the mitochondria. Acetyl-CoA is oxidized to carbon dioxide and reduces the important coenzymes nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD). Reduction of these nucleotides captures the energy from fuel oxidation. They in turn become substrates for the final pathway, oxidative phosphorylation, where the electrons they carried reduce molecular oxygen through a chain of electron transport reactions, providing the energy for the synthesis of ATP. While oxygen is essential for metabolism, it can also cause oxidative stress and widespread tissue damage during inflammation. Powerfulantioxidant defenses exist to protect cells and tissues from damaging effects of oxygen.

Metabolism continuously cycles between fasting and post-eating modes

The direction of the main pathways of carbohydrate and lipid metabolism changes in response to food intake. In the fed state, the active pathways are glycolysisglycogen synthesis,lipogenesis and protein synthesis, rejuvenating tissues and storing the excess of metabolic fuel. In the fasting state, the direction of metabolism reverses: glycogen and lipid stores are degraded through glycogenolysis and lipolysis, providing a constant stream of substrates for energy production. As glycogen stores became depleted, proteins are sacrificed to make glucose through gluconeogenesis, guaranteeing a constant supply, while other biosynthetic pathways are slowed down. Common conditions such as diabetes mellitus, obesity and atherosclerosis that are currently major public health issues, result from impairment of fuel metabolism and transport.

Tissues perform specialized functions

Such functions include muscle contraction, nerve conduction, bone formation, immune surveillance, hormonal signaling, maintenance of pH, fluid and electrolyte balance, and detoxification of foreign substances. Specialized compounds, such as glycoconjugates (glycoproteins, glycolipids and proteoglycans), are needed for tissue organization and cell-to-cell communications. Recent progress in understanding cellular signaling systems has improved our insight into cell growth, and repair mechanisms. Their time-dependent decline leads toaging, and their failure causes diseases such as cancer.

The genome underpins it all

The genome provides the mechanism for conservation and transfer of genetic information, through regulation of the expression of constituent genes and their control of protein synthesis. The synthesis of individual proteins is controlled by information encoded in deoxyribonucleic acid (DNA) and transcribed into ribonucleic acid (RNA), which is then translated into peptides that fold into functional protein molecules. The spectrum of expressed proteins and the control of their temporal expression during development, adaptation and aging are responsible for our protein make-up. In the last few years bioinformatics, genome-wide association studies and progress in understanding of epigenetics, provided truly fascinating insights into the complexity of genetic regulatory networks. Further, applications of recombinant DNA technology have revolutionized the work of clinical laboratories during the last decade. The recent ability to scan the entire genome and the potential of proteomics and metabolomics provides yet new insights into gene-driven protein synthesis.

This chapter is summarized in Figure 1.1. To think about it, the figure resembles the plan of the London Tube (see Further reading). Look at it now and don't be intimidated by the many as yet unfamiliar terms. Refer back to this figure as you progress in your studies, and you will notice how your understanding of biochemistry improves.

image

FIG. 1.1 Biochemistry: all in one.
This figure has been designed to give you a bird's-eye view of the field. It may help to structure your study or revision. Refer back to it as you study the following chapters and see how you gain perspective on biochemistry. GABA, γ-aminobutyrate; glycerol-3-P, glycerol-3-phosphate; CoA, coenzyme A; TCA cycle, tricarboxylic acid cycle; cyt, cytochrome; FP, flavoprotein; Q, coenzyme Q10; ATP, adenosine 5'-triphosphate.

What this book is – and isn't

In today's medical education, acquired knowledge should be a framework for career-long study. Studying medicine piecemeal by narrow specialties is seen as less valuable than integrated learning, which places acquired knowledge in a wider context. This book attempts to do just that for biochemistry.

Keep in mind that Medical Biochemistry is not designed to be a review text or resource for preparation for multiple choice exams. These resources are provided separately on our website. This text is a strongly clinically oriented presentation of the science of biochemistry. It is a resource for your clinical career. It is shorter than many of the heavy tomes in our discipline, and it focuses on explanation of key concepts and relationships that we hope you will retain in your recall memory, and use in your future clinical practice.

As you study, remember that this is just one among the available textbooks for students and physicians. On our website, you can connect to other medical textbooks, moving readily from the biochemical aspects of a system or disease to its anatomy, physiology, pharmacology, clinical chemistry and pathology. Medical Biochemistry is also conveniently hyperlinked to other resources, such as clinical associations and key guidelines.

A textbook is a snapshot of rapidly changing knowledge

What only a few years ago was pure biochemical theory is now a part of the clinicians' vocabulary at the ward rounds and case conferences. A doctor (or a future doctor) does not learn biochemistry to gain theoretical brilliance: he or she learns it to be prepared for future developments in clinical practice.

We wrote Medical Biochemistry because we are convinced that understanding biochemistry helps in the practice of medicine. The question we asked ourselves many times during the writing process was ‘how could this piece of information improve your clinical reasoning?’ The text constantly links basic science to situations which a busy physician encounters at the bedside, in the doctor's office and when requesting tests from the clinical laboratories, which is what you will have to do when you start practicing medicine. We hope that the concepts you learn here will help you then – and benefit your patients.

Further reading

Cooke, M, Irby, DM, Sullivan, W, et al. American medical education 100 years after the Flexner report. N Engl J Med. 2006; 355:1339–1344.

Dominiczak, MH. Teaching and training laboratory professionals for the 21st century. Clin Chem Lab Med. 1998; 36:133–136.

Jolly B, Rees L, eds. Medical education in the millennium. Oxford University Press: Oxford, 1998; 1–268.

Ludmerer, KM. Learner-centered medical education. N Engl J Med. 2004; 351:1163–1164.

Tube map. www.tfl.gov.uk/assets/downloads/standard-tube-map.pdf.