Simon A. Whawell, BSc (Hons) PhD DipEd FHEA FRCPath is Reader in Oral Science at the School of Clinical Dentistry, The University of Sheffield, UK.
Daniel W. Lambert, BSc (Hons) PhD FHEA is Reader in Molecular Cell Biology at the School of Clinical Dentistry, The University of Sheffield, UK.
Daniel W. Lambert and Simon A. Whawell
School of Clinical Dentistry, University of Sheffield, Sheffield, UK
- To understand the basis of molecular structure and bonding.
- To outline the basic structure and function of proteins, carbohydrates, lipids and nucleic acids.
- To be able to describe the biological role of enzymes and explain how their activity is regulated.
- To understand basic energy-yielding pathways and how they are controlled.
An understanding of basic biomolecule structure and function provides a foundation for all normal cell and tissue structure and physiology. The structure of biomolecules present in the human body closely relates to their function, as is the case for cells and tissues. In disease, drugs can be used that target specific biochemical pathways, so an appreciation of biochemistry underlies patient care as well as the diagnosis, prognosis and treatment of disease.
As complex as the human body is, it is heavily dependent on just four atoms for its composition: carbon, hydrogen, nitrogen and oxygen. These atoms form structurally diverse groups of biologically important molecules, their structure always relating to their function in the same way that the cells and tissues of the body are adapted. Biomolecules commonly take part in relatively simple reactions which are subject to complex control to finely tune the essential processes that they mediate. Biomolecules are often large polymers made up from smaller molecular monomers and even though there are thousands of molecules in a cell there are relatively few major biomolecule classes. Fatty acids, monosaccharides, amino acids and nucleotides form di- and triglycerides, polysaccharides, proteins and nucleic acids respectively. Small molecules are also important to biology, as we will see; adenosine triphosphate (ATP), for example, stores energy for catabolic and anabolic process and nicotinamide adenine dinucleotide (NADH) is the principle electron donor in the respiratory electron transport chain.
Molecular bonds are dependent on the arrangement of electrons in the outermost shell of each atom, being most stable when this is full. This can be achieved by transferring electrons, which takes place in ionic bonding (e.g. NaCl) or by sharing electrons in a covalent bond. Biological systems are also crucially dependent on non-covalent bonds, namely hydrogen bonds (or H bonds), electrostatic interactions and van der Waals' forces. While these 'bonds' are associated with at least an order of magnitude lower energy than covalent bonds they are collectively strong and can have significant influence on biological reactions. Non-covalent bonds differ in their geometry, strength and specificity. Hydrogen bonds are the strongest and form when hydrogen that is covalently linked to an electronegative atom such as oxygen or nitrogen has an attractive interaction with another electronegative atom. They are highly directional and are strongest when the atoms involved are co-linear. Hydrogen bonds are important in the stabilization of biomolecules such as DNA and in the secondary structure of proteins. Charged groups within biomolecules can be electrostatically attracted to each other. Amino acids, as we will discuss later, can be charged and such electrostatic interactions are important in enzyme-substrate interactions. The presence of competing charged ions such as those in salt would weaken such interactions. Finally, the weakest of the non-covalent interactions is the non-specific attraction called the van der Waals' force. This results from transient asymmetry of charge distribution around a molecule which, by encouraging such asymmetry in surrounding molecules, results in an attractive interaction. Such forces only come into play when molecules are in close proximity and although weak can be of significance when a number of them form simultaneously.
Water, Water Everywhere
The human body is of course comprised mostly of water but it is worth mentioning the profound effects that water has on biological interactions. Two properties of water are particularly important in this regard, namely its polar nature and cohesion. A water molecule has a triangular shape and the polarity comes from the partial positive charge exhibited by the hydrogen atom and the partial negative charge of the oxygen. The cohesive properties of water are due to the presence of hydrogen bonding (Figure 1.1). Water is an excellent solvent for polar molecules and does this by weakening/competing for hydrogen bonds and electrostatic interactions. In biology, water-free microenvironments must be created for polar interactions to have maximum strength.
Figure 1.1 The chemical structure of water.
Amino Acids and Proteins
Proteins are polymers of amino acids and are the most abundant and structurally and functionally diverse group of biomolecules. They form structural elements within the cell and extracellular matrix, act as transport and signalling molecules, interact to enable muscles to contract and form the biological catalysts (enzymes) without which most cell functions would cease. Amino acids consist of a tetrahedral alpha C atom (Ca) attached to a hydrogen atom, amine and carboxyl groups and a substituted side group (R) (Figure 1.2a), which can be anything from a hydrogen atom to a more complicated structure. Amino acids are chiral and in biology all are the left-handed (L) isomers. Many possible amino acid structures exist but only 20 occur naturally and are used for protein synthesis. Some of these are synthesized in the body from other precursors and some amino acids have to come from our diet (called essential amino acids). Amino acids can be broken down to form glucose as an energy source and can also act as precursors for other molecules such as neurotransmitters.
Figure 1.2 (a) Peptide bond and (b) amino acid ionization.
Amino acids cannot be stored or secreted directly so must be broken down prior to their removal from the body. Their carbon skeletons may be converted to glucose (glucogenic amino acids) or acetyl-CoA or acetoacetate (ketogenic), which can be fed into the tricarboxylic acid (TCA) cycle, generating energy. The nitrogen is then removed in three steps starting with transfer of the amino group (transamination) to glutamate which is then converted to ammonia by glutamate dehydrogenase in the liver. Finally ammonia enters the urea cycle, a series of five main biochemical reactions that results in the formation of urea, which is excreted in urine. The urea cycle is a good example of a disposal system where 'feed-forward' regulation through allosteric activation of the enzymes involved results in a higher rate of urea production if there is a higher rate of ammonia production (see Allosterism later in this chapter). This is important given that ammonia is toxic and also explains why a high-protein diet and fasting, which results in protein breakdown, induce urea cycle enzymes.
Amino Acid Ionization
The amide and carboxyl groups and some side chains of amino acids are ionizable and their state is dependent on the pH (Figure 1.2b). If you were to titrate an amino acid, at low pH all groups are protonated, the amino group carries a positive charge and the carboxyl group is uncharged. As the pH increases the proton dissociates from the carboxyl group, half being in this form at the first pK value of around pH 2 (pK1 on Figure 1.2b). As the pH increases further the amino acid is zwitterionic with both positive and negatively charged groups. As the net charge is zero this is the isolelectric point of an amino acid (pI on Figure 1.2b). At the second pK of pH 9 (pK2 on Figure 1.2b) half of the amine groups carry charge and the overall charge is negative. Titration curves for amino acids are not linear around the pK values as there is resistance to changes in pH as the amino acids act as weak buffers. If there is an ionizable side chain present there would be a third pK value; acidic amino acids lose a proton at pH 4 and thus have a negative charge at neutral pH. For basic amino acids this occurs around pH 10 and thus such amino acids are positively charged at neutral pH.
Classification of Amino Acids
As the only difference between amino acids is the nature of the substituted side chain this determines the characteristics of the amino acid, such as the shape, size, charge, chemical reactivity and hydrogen bonding capability. This ultimately determines the structure and function of the protein polymer that the amino acids form. Amino acids can be classified according to their structure or chemical nature; the latter is summarized in Figure 1.3. Polar amino acids have uneven charge distribution even though they have no overall charge. The hydroxyl and amide groups are capable of hydrogen bonding with water or each other and thus these amino acids are...