Cover page

Table of Contents

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Title page

Copyright page

Preface

Contributors

Abbreviations

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Part 1: Cellular structure and function

1: Cells

Tissues

Cell division

Stem cells

2: Organisation of cell membranes

Cell membranes

Phospholipids

The lipid bilayer

Membrane proteins

Transport across membranes

3: Cell organelles

4: Protein biochemistry

Structure

Life cycle

5: Lipid biochemistry

Fatty acids

Triglycerides

Cholesterol

6: Carbohydrate biochemistry

Carbohydrate structure

Glucose

Polysaccharides

Glycogen

Structural carbohydrates

7: Basic mechanisms of drug action

Pharmacological targets

Drug–receptor interactions

Description of drug actions

Part 2: Cellular metabolism

8: General principles of cellular metabolism

Energy requirements

High-energy phosphates

Enzymes and regulation

9: Enzymes

Enzyme kinetics

Key enzymic activities

10: Central metabolic pathways

The Link Reaction – pyruvate dehydrogenase

The TCA cycle

The electron transport chain (ETC) and oxidative phosphorylation

11: Fat metabolism

Lipolysis

Metabolism of fatty acids

Ketone bodies

12: Glucose metabolism

Glucose uptake

Glucose metabolism

13: Amino acid metabolism

Amino acid synthesis

The amino acid pool and protein turnover

Aminoacidopathies

Part 3: Molecular and medical genetics

14: Principles of molecular genetics

Gene cloning

Libraries

Isolation of a specific DNA sequence

DNA sequencing

Practical applications

15: DNA and RNA

Deoxyribonucleic acid (DNA)

Ribonucleic acid (RNA)

16: Gene expression

Transcription

Translation

The genetic code

17: Medical genetics

Chromosome structure

Sources of genetic variation

Treatment of genetic disease

Part 4: Nerve and muscle

18: Cell excitability

Resting membrane potential (Vm)

The sodium pump (3Na+/2K+ ATPase)

Hypokalaemia

Hyperkalaemia

19: Nervous conduction

20: Synaptic transmission

General principles

Cholinergic transmission

Noradrenergic transmission

Ionotropic neurotransmission

Metabotropic neurotransmission

Inhibitory neurotransmission

Spinal reflexes

21: Autonomic nervous system

Parasympathetic control

Sympathetic control

Autonomic regulation

Co-transmission

22: Neuromuscular transmission

Neuromuscular junction (NMJ)

Neuromuscular blockers

Inhibitors of acetylcholinesterase (AChE)

Pathophysiology

Part 5: Respiratory system

23: Structure of the respiratory system

Upper respiratory tract

Lower respiratory tract

24: Respiratory physiology

Breathing

Lung compliance and elastance

Diffusion and gas exchange

Ventilation-perfusion coupling

25: Gas transport

Oxygen

Carbon dioxide

26: Control of breathing

Neural generation of ventilatory pattern

Acclimatisation to altitude and hypocapnia

Hypoxic drive dependence with hypercapnia

27: Acid-base physiology

pH

Acidosis, alkalosis and compensation

28: Respiratory pathophysiology

Obstructive respiratory deficits

Restrictive respiratory deficits

Part 6: Cardiovascular system

29: Structure of the cardiovascular system

30: Cardiac physiology

Initiation of the heartbeat

The electrocardiogram (ECG)

Cardiac cycle

Cardiac haemodynamics

Autonomic control of the heart

31: Cardiovascular physiology

Regulation of vascular tone

Capillary exchange

Venous return

32: Blood pressure

Nervous control of blood pressure and baroreceptor control

Volume control of blood pressure

Hypertension

33: Blood: 1

Control of blood production

Blood counts

Blood groups

Anaemias

34: Blood: 2

Coagulation and thrombosis

Leukaemias and lymphomas

35: Cardiovascular pathophysiology

Hypertension

Ischaemic heart disease

Chronic heart failure

Cerebrovascular disease

Part 7: Renal system

36: Structure of the renal system

Kidneys and ureters

Bladder and urethra

37: Renal physiology: filtration and tubular function

Filtration

Proximal convoluted tubule (PCT)

Loop of Henle

Distal convoluted tubule (DCT)

Late DCT and cortical collecting duct

38: Renal physiology: loop of Henle

Countercurrent multiplication

Distal nephron and actions of antidiuretic hormone, ADH

39: Regulation of body fluids

Antidiuretic hormone

Other hormones in renal excretion of salt and water

Disorders

Diuretics

40: Bladder function and dysfunction

Autonomic control

Somatic control

Micturition

Disorders of bladder function

Part 8: Digestive system

41: Structure of the gastrointestinal system

Digestive tract

Vasculature of the digestive tract

Innervation of the digestive tract

Accessory organs of digestion

42: Upper gastrointestinal physiology

Salivation

Gastric physiology

Dyspepsia

43: Lower gastrointestinal physiology

Duodenum

Jejunum and ileum

Large intestines

Motility

Pathophysiology

44: The liver

Liver function tests (LFTs)

Liver disease

Part 9: Endocrine system

45: Hypothalamus and pituitary

Regulation of endocrine secretion

Hormones of the hypothalamus and pituitary gland

Endocrine disorders

46: Endocrine pancreas

Diabetes mellitus (DM)

47: Thyroid gland

Parathyroid hormone and calcitonin

Thyroid hormones: thyroxine (T4) and tri-iodothyronine (T3)

Thyroid disorders

48: Adrenal glands and steroid hormones

Hormones of the adrenal medulla

Hormones of the adrenal cortex

Part 10: Reproductive function

49: The genital system

External genitalia

Internal genitalia

50: Reproductive physiology

Hormonal regulation of the menstrual cycle

Conception

Pregnancy

51: Human embryology

Fertilisation

Gastrulation

Organogenesis

Fetal period

Part 11: Central nervous system

52: Structure of the central nervous system

Brain

Meninges and cerebrospinal fluid

Spinal cord

53: The sensory system

Sensory receptors

Somatosensory system

Special sensation

54: The motor system

55: Hypothalamus and thalamus

Hypothalamus

Thalamus

56: Central nervous system function

Physiological roles of the CNS

Higher functions

Neurotransmitters and function

57: CNS disorders and treatments

Epilepsy

Parkinson's disease

Multiple sclerosis (MS)

Stroke

Pain

Dementia

Depression

Anxiety

Schizophrenia

Part 12: Infections and immunity

58: Pathogens

Bacteria

Viruses

Fungi

Parasites

Prions

59: Recognition of pathogens

Innate recognition

Adaptive recognition

60: Defence against pathogens

Extracellular microbes (e.g. bacteria)

Intracellular microbes (e.g. viruses)

Extracellular parasites (e.g. helminths)

Mucosal microbes

61: Integration of the immune response

Innate immunity

Adaptive immunity

62: Immunopathology

Type I hypersensitivity – atopic allergy

Type II hypersensitivity – cell or membrane reactive

Type III hypersensitivity – immune complex disease

Type IV hypersensitivity – cell-mediated hypersensitivity

63: Immunodeficiency disorders

The nature of immunodeficiency disorders

Phagocyte defects

Complement deficiencies

B lymphocyte and antibody deficiencies

T cell defects and severe combined immunodeficiencies (SCID)

Part 13: Cancer

64: Cancer

65: Chemotherapy

Appendix 1: Cross references to Medicine at a Glance (Davey)

Index

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Title page

Preface

The At a Glance series provides brief summaries of the medical curriculum for medical, pharmacy and nursing students. Recent changes in curricula at medical schools have reduced the emphasis on students learning large amounts of factual detail and now focus more on core knowledge. Courses have also moved away from the traditional discipline-based approach of studying anatomy, physiology, biochemistry, pathology and pharmacology as distinct preclinical subjects, and many courses are now integrated. This provides a seamless study of the key physiological systems. The purpose of Medical Sciences at a Glance is to reflect the modernisation of medical courses and, as such, provides a single text to support students.

To understand and practise medicine the student needs to have a grasp of underlying biomedical sciences, and this book is intended for the early years' students. It should also help as a refresher of the medical sciences as students enter clinical phases of their courses, as a thorough knowledge of the medical sciences inevitably underpins clinical practice. For example, to understand the ECG in clinical practice one needs to understand the relevant anatomy, the underlying electrical events and the cardiac cycle.

By providing the background in biomedical sciences this edition feeds directly into Medicine at a Glance (Edited by Patrick Davey). The aim of this book is to set out core material on which students can build a framework of learning and understanding. By using this book students should be able to define what they need to know and use the material as key summary points. It is all too easy for students to attempt to learn all lecture material superficially, but the key to medical studies is to understand the core material. We also feel that Medical Sciences at a Glance would be of use to students on the newer problem-based learning courses by setting a background against which students can define their own learning needs.

We hope that this text will help support early years' students getting to grips with physiological systems. We have deliberately limited the clinical content as this is the domain of the sister publication Medicine at a Glance, but have inevitably used some examples of diseases and treatment to place biomedical sciences in context.

The authors of Medical Sciences at a Glance are all from the University of Nottingham and all currently teach the relevant medical sciences to medical, science and pharmacy students.

Michael D Randall

Contributors

Dr Jane Arnold

University Teacher

School of Life Sciences

University of Nottingham

 

Dr Stuart Brown

Director of Biomedical Sciences Teaching

School of Life Sciences

University of Nottingham

 

Dr Steven Burr

Formerly University Teacher

School of Biomedical Sciences

University of Nottingham Medical School

Now Associate Professor in Physiology

Medical School

University of Plymouth

 

Dr Sue Chan

Lecturer in Cell Signalling

School of Life Sciences

University of Nottingham

 

Dr Chien-Yi Chang

Research Fellow

School of Life Sciences

University of Nottingham

 

Dr Fergus Doherty

Lecturer in Biochemistry

School of Life Sciences

University of Nottingham

 

Dr Lucy Fairclough

Lecturer in Immunology

School of Life Sciences

University of Nottingham

 

Dr James Lazenby

Research Fellow

School of Life Sciences

University of Nottingham

 

Dr Siobhan Loughna

Lecturer in Anatomy

School of Life Sciences

University of Nottingham

 

Dr Deborah Merrick

Lecturer in Anatomy

School of Life Sciences

University of Nottingham

 

Dr Ian Todd

Associate Professor and Reader in Cellular Immunology

School of Life Sciences

University of Nottingham

 

Prof Michael D Randall

Professor of Pharmacology

School of Life Sciences

University of Nottingham

 

Dr Sebastiaan Winkler

Associate Professor in Gene Expression

School of Pharmacy

University of Nottingham

Abbreviations

5-HT 5-hydroxytryptamine
AI angiotensin I
AII angiotensin II
AC adenylyl cyclase
AcCoA acetyl coenzyme A
ACE angiotensin-converting enzyme
ACh acetylcholine
AChE acetylcholinesterase
ACTH adrenocorticotropic hormone
ADCC antibody-dependent cellular cytotoxicity
ADH antidiuretic hormone
ADP adenosine diphosphate
AIDS acquired immune deficiency syndrome
ALT alanine aminotransferase
AMP adenosine monophosphate (AMP)
ANP atrial natriuretic peptide
AP action potential
APCs antigen-presenting cells
AST: aspartate aminotransferase
AT1 angiotensin II receptor type 1
AV atrioventricular
AVP arginine vasopressin
BNP b-type natriuretic peptide
BPH benign prostatic hypertrophy
BSE bovine spongiform encephalopathy
CABG coronary artery bypass graft
CAH congenital adrenal hyperplasia
cAMP cyclic adenosine monophosphate
CCK cholecystokinin
CCRs central chemoreceptors
cGMP cyclic guanosine monophosphate
CHF chronic heart failure
CJD Creutzfeldt–Jakob disease
CML chronic myeloid leukaemia
CNS central nervous system
CO cardiac output
COMT catechol-O-methyltransferase
COPD chronic obstructive pulmonary disease
Cox cyclooxygenase
CRH Corticotropin-releasing hormone
CSF colony-stimulating factors (e.g. G-CSF, granulocyte CSF)
CSF cerebrospinal fluid
CTLR C-type lectin receptors
CYP450 cytochrome P450
D dopamine receptor
DCT distal convoluted tubule
DHAE dehydroepiandrosterone
DHAP dihydroxyacetone phosphate
DHFR dihydrofolate reductase
DM diabetes mellitus
DPP-IV dipeptidyl peptidase IV
DVT deep vein thrombosis
dUMP deoxy uridine monophosphate
ECF-like enterochromaffin-like cells
ECG electrocardiogram
EDHF endothelium-derived hyperpolarising factor
EDV end diastolic volume
EGF epidermal growth factor
EPO erythropoietin
EPPs excitatory postsynaptic potentials
ER endoplasmic reticulum
ERV expiratory reserve volume
ESV end systolic volume
ETC electron transport chain
F Faraday's constant
FCR Fc receptors
FDC follicular dendritic cells
FEV1 forced expiratory volume in the first second
FSH follicle-stimulating hormone
FVC forced vital capacity
G-CSF granulocyte colony-stimulating factor
GFR glomerular filtration rate
GLP-1 glucagon-like peptide 1
GLUTs glucose transporters
GLUT2 glucose transporter 2
GLUT5 glucose transporter 5
GnRH gonadotrophin-releasing hormone
GPCR G-protein-coupled receptors
GTN glyceryl trinitrate
HAART highly active antiretroviral therapy
Hb haemoglobin
hCG human chorionic gonadotrophin
HDL high-density lipoprotein
HER2 human growth factor receptor-2
HIV human immunodeficiency virus
HLA human leucocyte antigens
HMG-CoA reductase hydroxyl-methylglutaryl coenzyme A reductase
hnRNA heterogeneous nuclear RNA
IC immune complex
IF intrinsic factor
If ‘funny’ current
IFN interferon
IHD ischaemic heart disease
IMM inner mitochondrial membrane
INR international normalised ratio
IPSP inhibitory postsynaptic potential
IRV inspiratory reserve volume
JVP jugular venous pressure
Kd dissociation constant
KIRs killer cell immunoglobulin-like receptor
KLRs killer cell lectin-like receptor
KM Michaelis-Menten constant
LDL low-density lipoprotein
LH luteinising hormone
LPS lipopolysaccharide
LTA lipoteichoic acid
LTD long-term depression
LT long-term potentiation
M-receptors muscarinic receptors
MAO monoamine oxidase
MAP mean arterial pressure
MCV mean corpuscular volume
MDR1 multidrug resistance 1
mEPP miniature end plate potential
MG myasthenia gravis
MHC major histocompatibility complex
MI myocardial infarction
mRNA messenger RNA
MT melatonin receptor
NA noradrenaline
nAChR nicotinic acetylcholine receptor
NADP nicotinamide adenine dinucleotide phosphate
NCR natural cytotoxicity receptor
NLR NOD-like receptor
NK natural killer
NMDA N-methyl-D-aspartate
NMJ neuromuscular junction
NO nitric oxide
NSAIDs non-steroidal anti-inflammatory drugs
NTS nucleus tractus solitarius (nucleus of the solitary tract)
PAMP pathogen-associated molecular pattern
PAO2 arterial oxygen
PC phosphatidyl-choline
PACO2 arterial carbon dioxide
PCV packed cell volume
PCRs peripheral chemoreceptors
PCT proximal convoluted tubule
PDE phosphodiesterase
PDH pyruvate dehydrogenase
PE phosphatidyl-ethanolamine
PEF peak expiratory flow
PEFR peak expiratory flow rate
PFK-1 phosphofructokinase-1
PGI2 prostacyclin
PI phosphatidyl-inositol
PIF peak inspiratory flow
PL phospholipase
PPAR-γ peroxisome proliferator-activated receptor-gamma
PPI proton pump inhibitor
PRR pathogen recognition receptor
PS phosphatidyl-serine
PTH parathyroid hormone
R gas constant
RAAS renin-angiotensin-aldosterone system
RBC red blood cell
RER rough endoplasmic reticulum
RhD rhesus antigen
RLRs RIG-like helicase receptors
rRNA ribosomal RNA
SAN sinoatrial node
SCID severe combined immunodeficiencies
SCN suprachiasmatic nucleus
SIADH syndrome of inappropriate antidiuretic hormone secretion    
sIg surface immunoglobulin
SGLT1 the sodium-glucose transporter protein 1
SSRI serotonin-selective reuptake inhibitor
TAG triacylglycerol
Tc T cytotoxic
TCA tricyclic antidepressant
TCA cycle tricarboxylic acid or Krebs cycle
TCR T cell receptor
TIA transient ischaemic attack
Th T helper
TLC total lung capacity
TLR toll-like receptors
TNF-α tumour necrosis factor-alpha
TPR total peripheral resistance
tRNA transfer RNA
TSG tumour suppressor gene
V rate of reaction
VC vital capacity
VEGF vascular endothelial growth factor
VIP vasoactive intestinal polypeptide
VLDL very low-density lipoprotein
Vm resting membrane potential
Vmax maximum rate of reaction
VOCs voltage-operated channels
V/Q ventilation-perfusion
vWF Von Willebrand's factor
UCP1 uncoupling protein 1
UTI urinary tract infection

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1

Cells

Sebastiaan Winkler

c1-fig-5001

A cell is the smallest functional and structural unit capable of replicating itself. As such, a cell is considered the basic unit of life. The boundary of a cell is the plasma membrane (see Chapter 2), while the cytoskeleton provides structural support (Figure 1.1). Cells of the human body have a characteristic nuclear compartment, which contains the genetic material, and are thus classified as eukaryotic cells as opposed to prokaryotic bacterial cells, which do not contain a nucleus. Cellular structures with specific functions, organelles, are discussed in Chapter 3.

Tissues

There are more than 200 different types of cells in the human body. These types are highly specialised (differentiated) to carry out specific functions. Groups of cells carrying out a similar function and forming a structure are called tissue. Different tissues combine to form organs. There are four main types of tissue.

Cell division

The mass and volume of tissues can increase by cell growth, the increase of cell mass and volume by taking up nutrients and synthesising new cell structures, and cell proliferation, the increase of cell numbers by cell division. There are two types of cell division.

When cells receive signals to divide they progress through the cell cycle (Figure 1.2). In adult tissue, most cells reside in the interphase. The interphase can be further divided into three phases. In the G1 phase (first gap phase), cells prepare for the duplication of the genetic material. When cells start duplicating their DNA, they progress through the S phase (synthesis phase). Following the G2 phase (second gap), cells undergo mitosis (M phase). Compared with the interphase, the mitotic phase is very short. Mitosis (Figure 1.3) can be separated into the following distinct stages.

During mitosis, the division of the cytoplasm between the two daughter cells is called cytokinesis. Cytokinesis starts during prophase, but is not completed until after the end of telophase when the two daughter cells have formed.

Stem cells

Stem cells are undifferentiated cells with two characteristics.

Stem cells are pluripotent if they retain the ability to differentiate into all cell types and tissues. For example, embryonic stem cells are pluripotent stem cells derived from early-stage embryos. Adult stem cells are not pluripotent, but are more specialised and can only form one or several tissues. For example, adult haematological stem cells isolated from the bone marrow can differentiate into the various cell types found in blood. Other adult stem cells are more specialised, e.g. skin stem cells found in the epidermis, which can only differentiate into skin cells. Induced pluripotent stem cells are derived from differentiated tissue that is genetically reprogrammed to return to their undifferentiated state.

2

Organisation of cell membranes

Sebastiaan Winkler

c2-fig-5001

Cell membranes

Cell membranes are large cellular structures that constitute the boundary of a cell or a cell organelle. In contrast to proteins or nucleic acids, membranes are not made up of polymers, but a large number of diverse, relatively small molecules that form non-covalent interactions.

Phospholipids

The principal building blocks of cell membranes are a variety of compounds that are collectively known as phospholipids. Phospholipids are composed of three different parts: the backbone, a polar head group and a fatty acid chain (Figure 2.1). Different combinations of backbone, head groups and fatty acids result in a wide variety of phospholipids. In mammalian cells, glycerol is the backbone of the most abundant class of phospholipids, termed phosphoglycerides, although sphingolipids are also abundant. Backbone moieties have three hydroxyl groups, which are available for the conjugation of the polar head group, and two fatty acid chains. The polar head group is linked to the backbone via a phosphoester bond. In addition, two fatty acids are conjugated to the remaining hydroxyl groups of the backbone. The fatty acids can be broadly divided into two groups. The saturated fatty acids do not contain double bonds and always contains an even number of carbon atoms (usually 16–20). Due to the free rotation of the single carbon–carbon bonds, these lipid chains can adopt linear configurations. By contrast, the unsaturated fatty acids contain one or more double bonds. When the groups that lie on either side of the double bond are on opposite sides of the double bond (trans configuration) they are called trans fatty acids (Chapter 5). Like unsaturated fatty acids, trans fatty acids can adopt (near) linear configurations. However, when the groups next to the double bond are on the same side of the double bond (cis configuration) the fatty acids adopt very different shapes. The cis fatty acids have characteristic bends and cannot adopt linear configurations (Chapter 5).

A characteristic feature of the phospholipids is that they are amphipathic: they are both hydrophilic (due to the polar head group) and lipophilic (due to their fatty acid chain).

The lipid bilayer

Due to their amphipathic nature, phospholipids spontaneously organise in such a way that they form two sheets, with the polar head groups facing the aqueous exterior and the fatty acid chains forming a hydrophobic core (Figure 2.2). This structure is termed the lipid bilayer. Phospholipids can diffuse freely in the lipid bilayer, which behaves as a two-dimensional fluid. The lipid bilayer is asymmetrical, because phospholipids on one side of the bilayer do not freely flip to the other side. Thus, on the outside of cell membranes, phospholipids with PC head groups are enriched, while the cytoplasmic side is enriched with PE and PS lipids. The composition of the lipid bilayer is not homogeneous. The properties of cell membranes is influenced by the properties of the locally enriched phospholipids, e.g. the length of fatty acid chains influences the thickness of the lipid bilayer, and the presence of phospholipids containing cis fatty acids reduces the density of phospholipids in the lipid bilayer.

Sterols are another class of lipid components. Cholesterol is the most abundant sterol found in cell membranes (Chapter 5). Cholesterol impacts on the fluidity of the membrane: low concentrations of cholesterol can increase fluidity, whereas high concentrations of cholesterol can have the opposite effect.

Membrane proteins

Proteins are a third group of molecules found in cell membranes. There are three classes of membrane proteins (Figure 2.3).

Membrane proteins do not diffuse freely in the lipid bilayer. Additional polar and non-polar interactions with phospholipids and cholesterol, as well as other membrane proteins, result in order around membrane proteins. These areas, which are more structured and packed compared with the lipid bilayer, are termed lipid rafts. Lipid rafts can diffuse freely in the lipid bilayer.

Transport across membranes

The lipid bilayer is a semi-permeable barrier that prevents the free diffusion of molecules. Gases, such as O2, N2 and CO2, as well as small polar molecules, can diffuse through the membrane. In contrast, the lipid bilayer is impermeable to large polar molecules or charged molecules. Three types of membrane proteins facilitate and control the transport of ions and small molecules, including sugars and amino acids, across cell membranes (Figure 2.4).

3

Cell organelles

Sebastiaan Winkler

c3-fig-5001

Organelles (Figure 3.1) are most commonly defined as specialised structures within a cell that are enclosed by a membrane. The most prominent organelle of eukaryotic cells is the nucleus, which stores the maternally and paternally inherited DNA. The DNA in the nucleus is bound to proteins (histones) to form chromatin fibres, which help package the DNA into the nucleus. The DNA is used as a template for messenger RNA in a process called transcription (Chapter 16). The nucleus is separated from the cytoplasm by the nuclear envelope, a double membrane structure. Transport of proteins and nucleic acids (ribonucleic acid, RNA) between the nucleus and the cytoplasm is facilitated by the nuclear pore complex. The nucleoskeleton provides structure and rigidity to the nuclear compartment. One or several clearly distinct regions (nucleoli) are visible within the nucleus using light microscopy. The nucleoli are sites of ribosomal RNA production.

Mitochondria are the major sites of O2 consumption. The majority of ATP (adenosine triphosphate), a central source of energy in cells, is produced by mitochondria. The outer membrane is smooth, while the inner membrane forms characteristic folds (cristae). While the initial stage of glycolysis, in which glucose is converted into pyruvate, takes place in the cytosol, mitochondrial enzymes associated with the cristae and present in the mitochondrial matrix transfer energy present in pyruvate and fats to ATP via the tricarboxylic acid (TCA) cycle and the electron transport chain (Chapter 10). Mitochondria contain specialised enzymes encoded by mitochondrial DNA, which resides in the mitochondrial matrix. Because mitochondria in the embryo are derived from the egg cell, mitochondrial DNA is maternally inherited.

The endoplasmic reticulum (ER) is membrane-containing structure surrounding the nucleus and attached to the nuclear envelope. Based on its appearance on electron micrographs, the endoplasmic reticulum is divided into the smooth endoplasmic reticulum and rough endoplasmic reticulum. The smooth endoplasmic reticulum is associated with phospholipid biosynthesis, storage of Ca2+ ions and other processes. The rough endoplasmic reticulum is associated with many ribosomes. Whereas ribosomes present in the cytosol produce soluble proteins that will function in the cytosol, ribosomes associated with the RER are involved in the synthesis of three classes of proteins.

Many proteins undergo post-translational modifications in the lumen of the ER. Branched sugar chains are attached to serine and asparagine residues (glycosylation). The formation of the covalent bond between two cysteine residues (disulfide bond) also occurs in the lumen of the ER.

Proteins synthesised by the RER are transported in transport vesicles to the Golgi complex, a network of membrane-enclosed compartments. Both proteins inserted in the ER membrane as well as proteins present in the lumen of the ER are transported in this manner to the cis-Golgi network. The proteins in the Golgi continue to be transported in membrane-enclosed vesicles to the trans-Golgi network. At least two processes are carried out in the Golgi network.

Endosomes are formed from endocytic vesicles, which are pinched off from the plasma membrane facilitating transport from the plasma membrane into the cell (endocytosis). Often, membrane receptors bound to their ligands are involved. The lumen of endosomes gradually becomes more acidic and the contents of endosomes are finally delivered to lysosomes.

The lysosome is a membrane-enclosed organelle specialised in the degradation and recycling of proteins, lipids, polysaccharides and nucleic acids. Many lysosomal enzymes catalyse hydrolysis reactions. The products of these reactions, such as simple sugars and amino acids, are re-used in the cytosol.

Peroxisomes are enclosed by membranes and consume significant amounts of O2, which is used to form hydrogen peroxide (H2O2). The enzyme catalase uses H2O2 for oxidative degradation of diverse substrates, including large fatty acids and ethanol. Peroxisomes are also important for the synthesis of the main phospholipid components of myelin. This role of peroxisomes is especially relevant for the function of nerve cells.

The system containing the numerous vesicles involved in transport between the ER, Golgi, endosomes, lysosomes and peroxisomes is collectively referred to as the membrane trafficking network.

In addition, there are a number of structures that are not enclosed by membranes, but which have clearly identified roles. These structures are sometimes classified as non-membrane organelles.

4

Protein biochemistry

Fergus Doherty

c4-fig-5001

Proteins are polymers of the 20 common L-amino acids and constitute about 16% of the body weight of the average adult. Proteins have a wide range of functions in the human body, including as enzymes, motors, transporters, receptors and other signalling factors; components of the immune system; as well as structural components of cells and the extracellular matrix. Proteins do not serve as a primary energy store, although during starvation protein is degraded, especially in skeletal muscle, to release amino acids, the carbon skeletons of which can be used for gluconeogenesis in the liver (Chapter 12).

Structure

L-amino acids are combined in proteins by the formation of a bond between the carbon atom of the α-carboxyl group of one amino acid and the nitrogen of the α-amino group of the next. This is the peptide bond. A small number of amino acids (residues) joined in this way are called a peptide, a larger number a polypeptide. The electrons of the double bond of the carbonyl group are delocalised, giving the C–N peptide bond a partial double bond character, which restricts rotation about this bond and influences how polypeptides fold in space. The sequence of amino acids joined by peptides in a polypeptide, the primary sequence or structure, is determined by the sequence of the gene coding for that polypeptide, and in turn determines how the polypeptide folds in three-dimensional space (Figure 4.1). Primary sequence is always written from the free amino terminus on the left to the free carboxyl terminus on the right, which is the direction of protein synthesis. The structure of polypeptides exhibits a hierarchy, with the primary structure being the first level.

The next level of polypeptide or protein structure is the secondary structure (Figure 4.2), which describes some of the folding of the polypeptide in 3D space. Regions of polypeptides can adopt three types of secondary structure determined by the amino acid sequence. The α-helix (Figure 4.2a) has a right-handed thread with 3.6 amino acids per turn and is stabilised by hydrogen bonds between every fourth amino acid formed by the carbonyl and NH groups of peptide bonds. Amino acid side chains point out from the helix. β-strands are pleated structures that hydrogen bond together to form β-sheets with amino acids side chains positioned above or below the plane of the sheet, while the strands can run in the same (parallel) or opposite (anti-parallel) directions. Secondary structure also includes β-turns (Figure 4.2b), consisting of about 4–7 amino acids, which introduce a turn into the backbone of the polypeptide (e.g. between two anti-parallel β-strands). Polypeptides can also include regions lacking in the clearly defined secondary structures described, such as various loops, random coils, or disordered regions. An example of a polypeptide containing mostly α-helix is myoglobin, while some membrane channel proteins contain extensive β-sheets that form a barrel-like structure.

Tertiary structure describes how secondary structures are arranged in space with respect to each other and the overall ‘fold’ of the polypeptide, and is stabilised mainly by hydrophobic interactions. Soluble proteins (Figure 4.3) generally fold to hide hydrophobic amino acid side chains in the interior away from water, while polypeptides resident in membranes (Figure 4.4) tend to have hydrophobic amino acids in the membrane-spanning regions, with side chains facing the interior of the membrane. Many polypeptides fold to create distinct domains, which are associated with a particular function, for example binding ATP, and similar domains can be found in different polypeptides with this function. The final level of protein structure is quaternary and describes how many polypeptide chains are grouped together in the functional protein, held together largely by non-covalent interactions, although inter-chain disulfide bonds between cysteine residues can play a role. Individual polypeptides in proteins are called subunits; although many proteins will have only one subunit many have two, four, or more.

Life cycle

Proteins are synthesised (translated) from amino acids on ribosomes using the information transcribed from DNA on to mRNA (Chapters 15 and 16). Following translation, covalent modification may occur (proteolytic processing, formation of disulfide bonds, or modification of some amino acid side chains, e.g. hydroxylation of proline in collagen). Some proteins will be secreted from the cell (e.g. extracellular matrix proteins). Intracellular proteins are subjected to degradation to amino acids at various rates, depending on the protein, so different proteins have different half-lives. Degradation is carried out by the ubiquitin-proteasome system, which regulates the concentration of many regulatory proteins, or in lysosomes. Proteins that have become damaged or fail to fold correctly are rapidly degraded to prevent their accumulation. The accumulation of undegraded ‘abnormal’ proteins can be lead to disease, for example prion proteins in the transmissible encephalopathies (BSE in cows, CJD in humans) and amyloid in Alzheimer's disease.

5

Lipid biochemistry

Jane Arnold

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Lipids are defined as organic molecules that share the property of being water insoluble but are highly soluble in organic solvents. They are structurally diverse and have many different functions, including:

Some of the most important biological lipids include fatty acids, triglycerides and cholesterol.

Fatty acids

Structure

Fatty acids are composed of a long hydrocarbon chain with a terminal carboxylic acid. They normally contain between 14 and 24 carbon atoms and have the general formula CH3(CH2)nCOOH (Figure 5.1a). They exist in a saturated (no double bonds in hydrocarbon chain), monounsaturated (one double bond) and polyunsaturated (two or more double bonds) form. Most of the double bonds in naturally occurring unsaturated fatty acids exist in a cis configuration (same side of the double bond) (Figure 5.1b). A trans configuration (opposite sides of the double bond) can also occur (Figure 5.1c). The addition of the double bond causes a bend or kink in the hydrocarbon chain, which impacts on the packing of these molecules and causes a reduction in the melting point of the molecule. For example, stearate, an 18C saturated fatty acid has a melting point of 69°C, while oleate, a monosaturated 18C fatty acid, has a melting point of 13°C. This is important when considering the role of fatty acids in cell membrane structure (Chapter 2). The chain length also affects the melting point; the longer the chain length, the higher the melting point.

Nomenclature

The naming of fatty acids is slightly confusing, as while systematic names exist, naturally occurring fatty acids are generally called by their common names. A numbering system is also used, whereby the left-hand number depicts the number of carbon atoms and the right hand number reflects the number of double bonds in the hydrocarbon chain. Table 5.1 lists some of the naturally occurring common fatty acids. Normally the name of the fatty acid ends in ‘oic acid’, but most fatty acids are ionised at physiological pH (COO instead of COOH) and end in ‘ate’. For example, palmitic acid (CH3(CH2)14COOH) will occur physiologically as palmitate (CH3(CH2)14COO).

Sources

Most fatty acids are ingested in the diet in the form of triglycerides. However, there is a de novo pathway of fatty acid synthesis in the liver where acetyl coenzyme A (acetylCoA) is used as the building block to produce long-chain fatty acids. Two important fatty acids, however, cannot be synthesised in the body and must be taken in the diet. These are linoleate and linolenate (Table 5.1), which are collectively called the omega fatty acids. Linoleate (omega 6) is a precursor to a family of signalling molecules known as prostaglandins, while linolenate (omega 3) is an important constituent of some specialised membranes (e.g retinal cell membranes).

The majority of trans fatty acids are produced as a product of hydrogenation of vegetable oils (e.g. in margarine production). Ingestion of trans fatty acids is of concern as they have been linked to an increased risk of coronary heart disease.

Functions

Component of cell membranes – fatty acids and modified forms of fatty acids are an important component of the lipid bilayer of membranes (Chapter 2).

In metabolism – fatty acids can either be obtained from the diet or can be synthesised from AcCoA. These can then be stored as triglycerides in adipose tissue (see below). The energy stored in these molecules can then be released by beta oxidation to produce large quantities of ATP (see Chapter 11).

In cell signalling – fatty acids are used in a number of ways in cell signalling.

Triglycerides

Triglycerides are a major fuel source for the body and are commonly referred to as fats (if solid at room temperature) or oils (if liquid at room temperature). Triacylglycerol (TAG) contains a glycerol backbone to which three fatty acids chains are attached by an ester linkage. The three fatty acids can be identical (simple TAG) or different (mixed TAG) (see Figure 5.2

TAGS can be obtained through the diet or made from de novo fatty acids and will be stored in the cytoplasm of adipose cells. As these molecules are hydrophobic, they contain very little water and so are an efficient way of storing energy. They can be mobilised to break down and produce ATP under the appropriate hormonal signals (see Chapter 10).