Chemical

and biomolecular basis of pathophysiology

Objectives/main points of each lecture segment:
1. Chemical Foundations of Life
a. Review the periodic table, focus on the elements most found in the body – need to
emphasize similar properties between elements arranged in COLUMNS
b. Review atomic structure, subatomic particles and their charges, nature of the electron
shell
c. Chemical reactivity depends on electron shell filling
d. Ion formation
e. Role of ions in the body, including acids and bases
f. Covalent bond structures and formation
2. Chemical patterns in pathophysiology
a. Describe the differences in electron sharing between nonpolar and polar covalent
bonds
b. Identify the way that unequal electron sharing between oxygen and hydrogens
contributes to the bent shape of water molecules
c. Aqueous solutions involve hydrogen bonding
d. Predict chemical structures that characterize hydrophilic vs hydrophobic molecules
3. Organic chemistry foundations of pathophysiology
a. Identify the role of carbon as the foundational atom of life
b. List the major organic functional groups, their names and chemical structures
c. Describe three major types of biochemical reactions that characterize cell function and
give an example of each
4. 4.1 Biomolecules build from small to large: carbohydrates and lipids
a. Give examples of small organic molecules that will combine together to build large
biomolecules
b. Identify the generic formula for carbohydrates. Discuss the manner in which
carbohydrate structure explains its chemical nature (hydrophilic/polar)
c. List the functions of carbohydrates.
d. Describe the major types of lipids and compare and contrast their structure and
functions.
e. Identify the biological roles of lipoproteins as a class of biomolecules.
5. 4.2 Biomolecules build from small to large: Amino acids are the building blocks of proteins
a. Identify the core structure that is common to all amino acids – what organic functional
groups are represented?
b. List the subtypes (classes, or families) of amino acids and characteristics of each
subtype
c. Describe the roles of significant individual amino acids, with examples.
6. Segment 4.3 Biomolecules build from small to large: Proteins are the most complex
a. Describe the mechanism of peptide bond formation.
b. Identify the expected pattern of folding of globular proteins in an aqueous
environment
c. Define the 4 levels of protein structure
d. Describe the contribution of amino acid characteristics to a protein’s intermolecular
attractions
e. Use the terms ligand and allosteric in describing protein function
7. Segment 4.4 Biomolecules build from small to large: Nucleotides and Nucleic Acids
a. Identify the differences between a base and a nucleotide
 b. List the functions of nucleotides
c. Compare and contrast structural and functional aspects of DNA and RNA
d. Describe the principle of complementary base pairing and the specific pairs involved
in double-stranded DNA as well as DNA-RNA complementarity.

Notes on individual slides:

Seg- Slide Notes
ment
1 5 All matter is made up of different kinds of elements, as shown in the periodic table.
But only a few elements make up the molecules serving as building blocks for
organisms, including humans. These include carbon, hydrogen, oxygen, nitrogen,
phosphorus, and sulfur. Other elements function as ions and a few metals have
special roles in cells.
6 The smallest unit of structure that we will be concerned with in this course is the
atom. Atoms have a nucleus made up of one or more positively charged protons,
and a variable number of neutrons, as well as one or more negatively charged
electrons that are in continual movement around the nucleus.
8 Of these 4 biologically important atoms, note the number of electrons in their
outermost shells:
1. Hydrogen has one electron in the inner ring that has the capacity to contain two
electrons. Hydrogen is often bonded to carbon in biological molecules (sugars,
amino acids, fatty acids). Since hydrogen only needs to add one electron to have a
complete outer shell, it can only make single bonds with other atoms. When the
single electron is lost, hydrogen atom becomes hydrogen ion (H+), at which point it
is also known as a proton, because the only remaining particle is a single proton in
the nucleus. Protons are critically important for body acid-base regulation and for
acidification of the stomach for proper digestion.
2. Carbon has 4 electrons in its outer shell. This allows carbon to make four bonds
to other atoms in order to form the complex molecules that make up the body. All
life on earth is made up of carbon-based molecules consisting of carbon chains,
carbon rings, and branching carbon compounds.
3. Oxygen has 6 electrons in its outer shell, so it is able to make 2 single bonds (as
in H2O, water) , or one double bond. Oxygen is the main source of energy
production in the body, in the form of cellular and mitochondrial oxidative
metabolism. Addition to a single electron to oxygen creates the molecule
“superoxide anion free radical”. We will discuss the role of such “reactive oxygen
species” in lecture #3.
4. Sodium is a highly reactive metal atom. The reactivity is due to having a single
electron in its outer shell. When this electron is lost, sodium atom is converted to
sodium ion, Na+. Na+ is the major extracellular cation of biological fluids.
11 A chemical compound made up of charged particles (ions: one or more positive,
one or more negative) is referred to as a SALT. Examples are: sodium chloride,
shown here (NaCl), sodium bicarbonate (NaHCO3), calcium carbonate (CaCO3) and
others.
12 These are just some of the ions that play a major role in physiology at the
molecular level. Ions have a full plus or minus charge, +1 or -2, for example. Ca++
 and Mg++ are referred to as DIVALENT cations, since they carry two positive
charges. Ions are also called electrolytes. This is because they are able to conduct
an electric charge when they are dissolved in solution, generally in water. The table
depicts the differing ionic composition of the intracellular and extracellular fluid.
Sodium is the major cation of the extracellular fluid, and potassium is the principal
cation of the intracellular fluid. These gradients are maintained by the plasma
membrane sodium-potassium pump.
13 When salts are added to a polar solution like water, they dissolve. This means the
water molecules orient themselves around the ion in such a way that opposite
charges are close to each other. This is especially relevant when you consider that
the body is 70% water.
14 Ions are responsible for a host of physiologic responses, including propagation of
an action potential down a neuron; control of the cardiac conduction system, and
contractions of the heart; and digestion of food.
15 Remember that protons (hydrogen ions, H+) are found in extremely low
concentrations in body fluids. The pH value is the negative logarithm of that
concentration. At pH = 7.4, the concentration of H+ will be 4.0 x 10-8 M, a very low
concentration!
16 We will discuss amino acids later in this lecture. For now, recall that an amino acid
has a structure with a central carbon, to which 4 different chemical groups are
bonded: an amine group (NH2), a carboxyl group (COOH), a hydrogen atom, and a
4th group (R) that will vary in structure depending on the individual amino acid.
18- Covalent bonds can join atoms together to form molecules. This process involves
20 an energy-requiring chemical reaction, and can be described by a chemical
equation in terms of reactants and products. Covalent bonds involve sharing of
electrons such that each atom with it’s partially filled electron orbital shell has a
greater probability of having a filled orbital shell, due to the contribution of
electrons of the atom to which it is bonded. Covalent bonds can be single, double,
or triple, depending on the number of electron pairs shared between the bonding
atoms.
2 3 Covalent bonds may have an unequal sharing of electrons, depending upon their
atomic composition. Molecules with a partial positive and negative charge due to
unequal electron sharing are known as polar molecules. Water, shown above, is a
polar molecule, since the oxygen nucleus has 8 protons, thereby exerting a greater
pull on the electrons that it shares with hydrogen, giving the oxygen a partial
negative charge. Each hydrogen has less attraction to the electron it shares with
oxygen, giving it a partial positive charge.
5 Hydrogen bonding is a weaker attractive force than a chemical covalent bond. It
occurs when molecules (like water) that contain partial charges come into contact.
Although the attraction between water’s partially negative oxygen and partly
positive hydrogen is not strong enough to form a full-fledged ionic bond, when
many hundreds of hydrogen bonds are formed, very stable structures (like DNA)
can result.
6 We saw that the partial charges of polar molecules can attract each other.
Specifically, the partially positive charged hydrogen can be attracted to the partial
negative charge of an oxygen or nitrogen. This is called hydrogen bonding. Water
molecules hydrogen bond together, and water dissolves polar substances such as
 urea by forming hydrogen bonds with it. The hydrogen bonds are shown as a series
of dark pink lines between individual water molecules and different atoms within
the urea molecule.
7 The basis for most biological molecular interactions is through hydrogen bond
formation. Hydrogen bonding keeps the DNA double helix strands together.
Hydrogen bonding is also responsible for the appropriate folding of proteins and
for the attraction between proteins and other molecules that are meant to interact,
such as an antibody protein reacting with it’s target antigen, or a neurotransmitter
binding to it’s receptor.
9 Molecular polarity affects the structure and properties of biological molecules.
The cell membrane is a phospholipid bilayer that separates inside and outside of
the cell. The extracellular and intracellular environments are aqueous. So, the
membrane’s hydrophilic, or polar components face these environments, and the
middle area is hydropyhobic and non-polar. The hydrophobic membrane core
prevents mixing of extracellular and intracellular fluids.
3 3 The methyl group on the left is a common modifier of DNA, as well as of other cell
molecules. The methyl group is nonpolar and hydrophobic. The groups shown on
the right contain oyxgen and/or nitrogen (or sulfur). The polar nature of these
groups confer water solubility in compounds, due to their capability of forming
hydrogen bonds. These small groups have specific functions as part of the larger
biomolecules we will discuss next.
4 The presence of a sulfhydryl group in a molecule (usually a protein containing the
amino acid cysteine, confers the ability to form disulfide bonds. These often link
together portions of complex proteins (the hormone insulin contains three
disulfide bonds), however, they can form pathologically during oxidative stress in
cells.
5 – 7 Major types of biochemical reactions that characterize cell function
4.1 2 Biologic macromolecules are made up of smaller units, called monomers. Two
monomers connected together are called a dimer. Three or more monomers
connected together are called a polymer.
4 The OH groups (hydroxyl groups) are highly polar – the molecule of glucose shown
here is hydrophilic and soluble in water. Remember that the cell membrane’s lipid
core forms a barrier that does not permit glucose and similar polar molecules to
enter cells by simple diffusion.
5 A hexose sugar has 6 carbons, while a pentose sugar has only 5 carbons. All of these
monosaccharides are found in the body, although ultimately fructose and galactose
coming from dietary sources are converted into other molecules to produce body
energy.
8 Glycogen is a polymer of glucose molecules. Glycogen in liver and muscle cells
forms an energy reserve that lasts during a fast of 12-18 hours.
Here is a link to a fun video about carbohydrates:
https://www.youtube.com/watch?v=bwup7OIAJu4
9 Lipids and proteins of the cell membrane are often modified by the addition of
carbohydrate groups, forming glycolipids and glycoproteins. This process is called
glycosylation. Blood group antigens (A, B) are genetically encoded carbohydrate
structures attached to red blood cell membranes. Intracellular proteins can also
undergo glycosylation. Hemoglobin A1c is a test that measures how much
 hemoglobin has been glycosylated over the past 4-month span. This makes it a
good indicator of blood glucose control.
10 This is a fatty acid. The COOH or COO- (carboxyl) group at the top of the fatty acid
molecule is polar. The chain of carbon and hydrogen (a hydrocarbon chain) is
nonpolar and is not soluble in water. So, overall, a fatty acid is hydrophobic, since
the part with the oxygen is relatively small, compared to the rest of the molecule.
Since this molecule contains no double bonds, it is a SATURATED fatty acid.
11 Triglyceride is the primary storage form of fat in the body, in adipocytes, AKA fat
cells. Because it can store a great deal of energy with very little water, it is
considered the most efficient energy store (as compared to glycogen).
12 An amphipathic molecule is one that has a dual nature. One end or side of the
molecule is hydrophobic, the other end is hydrophilic. Phospholipids are
amphipathic, and their partial hydrophobic, partial hydrophilic nature is what
contributes to their role as the major structural molecules of cell membranes. Note
that the middle carbon of the glycerol backbone is bonded to an unsaturated fatty
acid, containing one double bond (it is monounsaturated).
13 This is how the phosopholipids are oriented in the lipid bilayer of the cell
membrane. Remember that the environment within and outside the cell is aqueous,
thus polar, while the core of the membrane is made up of fatty acids and is strongly
nonpolar.
15 The phospholipid bilayer of the cell membrane has proteins and cholesterol
imbedded in it. The proteins may serve as receptor sites or ion channels; the
cholesterol stabilizes the membrane. Here is a lipid song: Lipids:
https://www.youtube.com/watch?v=eB793h16R8A
16 The cell membrane is the interface between the inside of the cell and rest of the
body or the outside world. It receives chemical signals from the body. The
phospholipids embedded in the membrane receive these signals and may act as
messengers or induce the cell to alter its metabolism.
17 Membrane phospholipids also mediate inflammation via cell signaling. During
acute inflammation, the fatty acid arachidonic acid is chemically split from a
membrane phospholipid. The enzyme that does the splitting is called
phospholipase A2. The arachidonic acid is then processed by enzymes, either
cyclooxygenase or lipoxygenase, to ultimately form the inflammatory mediators
leukotrienes and prostaglandins.
4.2 2 Proteins are made up of chains of amino acids. There are 20 amino acids found in
all life forms. An amino acid that cannot be synthesized by the human body is
known as an essential amino acid.
3 With an R group consisting of a single hydrogen atom, glycine is the simplest and
smallest amino acid.
4 The acidic amino acids, aspartic acid and glutamic acid, have a carboxyl group in
the R group. The carboxyl group is a source of protons (H+), thus, they are acids,
because they are proton donors.
5 The basic amino acids, lysine, arginine, and histidine have amine groups that can
absorb a proton (H+) and become positively charged. Thus, they are bases, or
proton acceptors.
6 The hormone INSULIN, shown here, has several cysteines that contribute to folding
during protein synthesis and that hold together the final active protein (the darker
 blue circles indicate the amino acids of the mature insulin molecule). Insulin has
one intrachain and two interchain disulfide bonds.
7 Take note of the side chain structures that contain only C and H, no oxygen or
nitrogen. These are nonpolar, hydrophobic amino acids. The hydrocarbon side
chains of nonpolar amino acids favor interactions with hydrophobic environments.
Proteins that have distinct regions rich in hydrophobic amino acids are usually
found embedded in the plasma membrane. As we will see later, most cell receptors
are proteins that contain exactly 7 membrane-spanning regions. Those regions are
rich in hydrophobic amino acids.
8 As with other polar biomolecules, polar amino acids must contain an oxygen or a
nitrogen. Although these amino acids are not fully charged ions, they do have
partial charges, therefore, they are hydrophilic.
9 When a protein contains many acidic amino acids, it has a negative charge that can
attract positively charged amino acids and ions.
10 When a protein contains many basic amino acids, it has an overall positive charge
and can attract negative compounds such as negatively charged amino acids or
ions. Charged amino acids are also hydrophilic, readily soluble in water, similar to
ions (Na+, Cl-).
11 The hydroxyl-containing amino acids are particularly known for being the targets
of phosphorylation reactions.
Enzymes called protein kinases, when activated by second messengers or
hormonal signals, carry out an exchange reaction of removing the hydrogen from
the hydroxyl group, and adding a phosphate. Most protein kinases attach the
phosphate to the hydroxyl oxygen of SERINE or THREONINE. Special tyrosine
kinases phosphorylate proteins on their tyrosine hydroxyl oxygen. Tyrosine kinase
activity is associated with the insulin receptor, and also with many growth factor
receptors and oncogene proteins.
12 In addition to serving as the building blocks of proteins, amino acids can have
important functions as stand-alone small molecules in the cell. Certain amino acids
can be used to synthesize glucose through the metabolic pathways of
gluconeogenesis. Other amino acids are transformed by enzymes into
neurotransmitters and hormones.
4.3 2-3 In the cell process of translation, amino acids line up and are chemically joined by
peptide bonds in ribosomes. The formation of peptide bonds between adjacent
amino acids results in the removal of a water molecule, as shown. The amino acid
side chains project from the peptide backbone at various angles. From this linear
structure, the next step in protein formation is folding. The amino acid sequence
determines the proper folding and final shape of the protein.
4 For proteins synthesized to be exported (such as albumin or antibodies), OR for
proteins of the intracellular fluid (enzymes), the proteins will ultimately be
surrounded by an aqueous environment (extracellular or intracellular fluid,
respectively). Such proteins tend to fold during or shortly after synthesis into a
conformation that positions nonpolar amino acid chains in the core of the protein
and polar or charged amino acid chains on the exterior surface of the proteins. In
this position, the outward facing amino acids can make hydrogen bonds with the
surrounding aqueous environment.
5-9 The 4 levels of protein structure reflect increasing degrees of complexity and
 organization. Protein folding is so crucial to proper protein function that cells have
a detection mechanism to determine whether protein folding is proceeding
normally (this system is described in more detail in module 3.
10 A major function of proteins is to bind to other molecules. For example, enzymes
have to bind to their specific substrates in order to carry out their biochemical
functions. The shape of a protein’s unique binding site depends on the amino acids
in that active site and whether they are charged, polar, or hydrophobic. These
properties will determine the ligand that can bind to the protein.
12- This information is for your review only.
16
16- Throughout the course, we will place great emphasis on specific enzymes and
17 transmembrane proteins responsible for cell and organ system function. Much of
pharmacology is based on the actions of transmembrane proteins such as
transporters (diuretics, antidepressants), ion channels (antiarrhythmics,
antihypertensives) and receptors (beta-blockers and beta-agonists, angiotensin
receptor blockers, antihistamines). Enzymes can also be drug targets (MAO
inhibitors, angiotensin-converting enzyme inhibitors).
4.4 2 A nucleotide is made up of:
A nitrogenous base
A ribose (5 Carbon) sugar
One or more phosphate groups
3 Bases are composed of one (pyrimidines) or two (purines) rings consisting of
carbons AND nitrogens in their structure. They are polar molecules, soluble in
water. During complementary base pairing shown in later slides, the pairs will
always consist of one purine and one pyrimidine, where the purine is somewhat
larger than the pyrimidine.
4 ATP is the principal molecule of energy storage in cells.
Individual nucleotides play a major role in cell signaling, particularly cAMP
(pictured here) and cGMP. In addition, GTP functions as a regulator of membrane
receptor signaling. Nucleic acids, both DNA and RNA, are long chains (polymers) of
nucleotides and are responsible for the transmission of genetic information and for
providing the instructions for protein synthesis through the processes of
transcription and translation.
5 The backbone of each long strand of DNA or RNA is formed by bonds between
sugar and phosphate molecules of adjacent nucleotides. The bases, adenine,
guanine, cytosine, and thymine, project away from the backbone and are available
for base pairing with their complementary bases.
8 DNA and RNA are very similar compounds. One difference exists in the ribose, or
sugar, making up each molecule’s nucleotide.
RNA is ribonucleic acid. DNA is deoxyribonucleic acid. The “deoxy” comes from
DNA having one less oxygen – at the 2’ position.
9 In humans, DNA is double stranded, and RNA tends to be single stranded.
11 The enzymes that synthesize both DNA and RNA can only add on new bases at the
free 3’ end of the molecule to elongate the growing chain. The terms 3’ and 5’ refer
to the numbering of the carbons in the ribose sugar part of the nucleotides.
12 Complementary* base pairing is the foundation of inheritance of genetic material
(through replication of DNA) and of genes on the DNA coding for synthesis of
 proteins (through transcription and translation).
13 The base pairs are held together with hydrogen bonds. Although individual
hydrogen bonds are relatively weak compared to covalent bonds, the millions of
base pairs found in strands of double-stranded DNA hold the strands tightly
together. The purine adenine forms 2 hydrogen bonds when it is aligned opposite
the pyrimidines thymine (in DNA) or uracil (RNA). The purine guanine forms 3
hydrogen bonds when it is aligned opposite the pyrimidine cytosine. This
complementarity is the basis of cellular genetic inheritance when DNA is replicated
prior to cell division (mitosis), and it is the basis of coding for protein structure
determined in the processes of transcription and translation.
14 As DNA is replicated, hydrogen bonds form between the newly synthesized strand
and the template strand, and the structural coils into its natural double-helical
spiral.
15 When looking at the two strands of a double-stranded DNA segment, the polarity of
the sugar-phosphate backbones are opposite. Each side has a 5’ end opposite to a 3’
end on the complementary strand. This is referred to as “antiparallel” structure.
16 The larger structure of human DNA is immensely complex. The double helix is
wrapped around proteins, coiled into a solenoid, then folded back onto itself in a
densely-packed lamp-brush pattern to fit genetic material into the tiny
chromosome.
17 If the DNA contained in all of the 46 chromosomes of a single human cell were
stretched, the resulting strand would be many meters long. Packing around
proteins and into chromosomes allows the genome to be contained in the nucleus.
18 Euchromatin – has greater acetylation and lower methylation of histones allowing
for a more relaxed structure. This allows greater access for transcription of genes.
Heterochromatin – has lower acetylation, greater methylation, allowing for tighter
packing and less gene expression activity.
19 Inability to metabolize phenylalanine, an essential amino acid. Normally
phenylalanine hydroxylase converts phenylalanine to tyrosine – when this enzyme
is not available, tyrosine also becomes an essential amino acid.
Tyrosine is needed for protein synthesis or catecholamine synthesis
20 Accumulation of phenylketones, and lack of tyrosine leads to the findings in PKU.
Because catabolism of phenylalanine must proceed via tyrosine, the absence of
phenylalanine hydroxylase leads to accumulation of phenylalanine. Tyrosine is also
a biosynthetic precursor for melanin and certain neurotransmitters, and the
absence of phenylalanine hydroxylase causes tyrosine to become an essential
amino acid.
Resources to help you learn this module’s content:
The University of Arizona’s Biology Project: www.biology.arizona.edu
Access the following links from the home page:
• Biochemistry
o Chemistry – click “next” repeatedly to go through the content, take notes, test
yourself using questions 2, 3, 4, 6, 7, 11, 12
o Large Molecules – go through the questions (1-12_
• Chemistry of amino acids – read content and click on the links to the left showing
structures of different classes
• Molecular biology/nucleic acids – try to answer questions 3, 4, 5, 8, 9, 10, 14