BCH2333 – Introduction to Biochemistry

Lecture 6

Carbohydrates
Lipids

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Carbohydrates:
General Formula: Mono- Oligo-
(CH2O)n

Poly-

Carbohydrates are one of the major sources of fuel that provide energy for life

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Monosaccharides: (CH2O)n, n≥3 (triose)

Monosaccharides are characterized by: (a) one carbonyl group
(b)
one or more hydroxyl groups
Two major classes of monosaccharides exist, differentiated by carbonyl group
Aldose Tautomers
Ketose

Slow
Slow

In addition to differentiating the carbonyl type, classification also differentiates carbon

number
Three carbons = tri Four = tet Five = pent Six =
hex Ribose Ribulose
So a monosaccharide class name is written as:
Carbonyl type-carbon
number-ose

e.g. Aldohexose =
Aldehyde – 6 carbon
For n≥4, the specific name of the ketose is derived from the aldose but
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Monosaccharides: Fischer Projections

1. Orient lowest priority away from you (H away)

2. Assign priority to remaining substituents based
on atomic number (low # is higher priority)
3. Determine direction of priority increase for
remaining substituents
D = clockwise L = counter-
clockwise If H is oriented towards you, you
Remember:
can flip the rule (clockwise = L)

2 3

1 1

3 2
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Monosaccharides: With aldoses of more than 3 carbons, multiple chiral

centres can arise in a single molecule.
A molecule with n chiral centres will have 2 n
stereoisomers (2 options per chiral position)
In these cases, the D/L naming convention relates to the
chiral C farthest from the carbonyl

Diastereomers occur when stereoisomers are not mirror

images of each other
When any of the chiral centres are not
equivalent between the two stereoisomers

There is no convention for naming diastereomers – the

specific names and associated chiral configurations must
just be learned and memorized.
Enantiomer
Diastereomer

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Monosaccharide Ring Structures:

With (CH2O)n, n=5 or 6, there is a preference to form a ring structure through intramolecular
hemiacetal formation
The C-O bond angles preclude rings of fewer members due to significant bond strain
Pentose Rings:

1
Pyran Furan
5
5
1 – anomeric C
* 1 *

a- D-Ribopyranose D-Ribose a- D-Ribofuranose

* Cyclization has created a new stereocenter at C 1, leading to anomers (recall form nucleic acids) or epimers

The cyclic stereochemistry can be represented as a Haworth projection:

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Conformational vs Configurational Isomers:

We talked about C2’- and C3’-endo states of nucleic acid sugars

C2’-endo C3’-endo These are furanose conformational isomers

base
base produced by difference in bond angle, and can
interchange readily in solution without breaking
covalent bonds.

There are specific “pucker” states of the pyranose sugars as well

Axial crowding
These are pyranose conformational isomers
produced by difference in bond angle, and can
interchange readily in solution without breaking
covalent bonds
Axial (a) = parallel to axis
Equatorial(e)=perpendicular to axis
The stereoisomers we talked about also have alternate structural states

Mutarotase
These are configurational isomers produced by
different bond orientations, and must have covalent
bond rearrangement (i.e. breaking and reforming) to
interchange. These isomeric changes occur through
the linear sugar intermediate, and can occur without
b-D-glucopyranose a-D-glucopyranose catalyst present.
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Monosaccharide Derivatives:
There are a large number of monosaccharides with a variety of roles in biochemistry, each one
bearing a specific chemical modification of their hydroxyl groups
Phosphate Esters: We have Oxidation Products: Oxidation can
seen the importance of these occur at C1 (gluconic acid) or C6
high energy bonds for coupling (glucuronic acid) chemically or
unfavorable biochemical enzymatically. These sugars have
reactions (e.g. ATP) Phosphorylation
important roles in metabolism and
b-D-glucose-1-phosphate
b-D-glucuronic acid detoxification.
Reduction Products: Reduction of
C6 Oxidation
the linear monosaccharide can
occur at the carbonyl, yielding the C1 Oxidation
Reduction
polyhydroxy alditol (parent sugar
prefix + ‘itol’ suffix)
D-gluconic acid D-gluconolactone

D-glucitol
b-D-glucose
Anomeric
Dehydration
Amination
+CH3OH
Amino Sugars: Sugars bearing an Glycosides: The conjugation of a sugar to
amine in place of a hydroxy group the hydroxy of another compound through
are important monomeric dehydration of the anomeric OH yields O-
components of oligo- and glycosides through a glycosidic bond (e.g.
polysaccharides, providing chemical DNA). Glycosidic anomers cannot
and functional diversity (parent interconvert in the absence of catalyst.
b-D-glucosamine
Methyl-b-D-glucose Their stereochemical stability makes these
sugar prefix + ‘amine’ suffix). The
amine groups provide functionally compounds key biochemical effectors (i.e.
important sites for further enzymatic
N-Acetylation toxins and/or drugs)
modifications (e.g. N-acetylation). b-D-N-acetylglucosamine
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Glycans:
Together with polysaccharides, oligosaccharides make up the glycans: key structural, energetic,
and signaling molecules in biochemistry.

Glycans are formed from monosaccharides joined by glycosidic bonds (anomeric OH dehydration)
Non-reducing Reducing
Glycosidic Linkage

b-D-galactosep(14)b-D-glucosep

Ring Configuration
Anomer form p =pyranose
f=furanose
Distinguishing Features: Anomer form

1. Sugar monomers and stereochemistry: Identify the anomeric carbons and assign stereochemistry (e.g. b vs a)
2. Carbons involved in the glycosidic linkage: The linkage is between two hydroxyl groups; most commonly, glycosidic
linkages between monosaccharides occur from the anomeric OH (C 1) to the OH groups of C1, C2, C4, or C6.
In lactose, the linkage is between b-D-Gal(C1) and b-D-Glu(C4): 14 linkage
3. The order of the monomer units (reducing vs. non-reducing ends): The presence of an anomeric carbon provides the
potential to form an aldehyde that can undergo chemical oxidation (or induce reduction). If the glycosidic linkage results
in a free anomeric carbon (e.g. glucose), then the monomer containing this anomeric carbon is the reducing end and
the resulting oligosaccharide is a reducing sugar. In this case, the monomer with no free anomeric carbon is the non-
reducing end (e.g. galactose). If the oligo contains a 11 linkage, there is no free anomeric carbon and the oligo is
non-reducing.
4. The configuration of the anomeric OH of each monomer: The configuration of the anomeric carbons involved in the
glycosidic linkage is key to determine the structure of the glycan, and its biochemical activity.
In lactose, both monomers are b form

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Glycosidic Bond Formation:

We previously talked about the formation of NTP + H2O NMP + PPi DG’=-31 kJ/mol
phosphodiester bonds between nucleotides to form DNAN+NMP DNA(N+1)+H2O DG’=25 kJ/mol
polynucleotides (e.g. DNA). This reaction occurs in the PPi + H2O 2 HPO42- DG’=-19 kJ/mol
forward direction because of the coupling of
monomers to high energy phosphate bonds, or DNAN+NTPDNA(N+1)+2HPO42- DG’=-25 kJ/mol
monomer activation.
DG’=15 kJ/mol
To overcome the thermodynamically unfavorable
reaction, sugar monomers are “activated” by
conjugation to uridine diphosphate (UDP) to form the
UDP-sugar (e.g. galactose). Phosphate ester
hydrolysis drives glycan formation.
DG’=-19 kJ/mol
ATP ADP UTP PPi 2Pi
UDP

+
Glycosyltransferase
(e.g. lactose synthase)

DG’=-31 kJ/mol DG’=0 kJ/mol DG’<0 kJ/mol

Enzyme-catalyzed phosphorylations and glycosylation reactions ensure that specific monomers are
combined in specific orientations. Main difference between glycans and proteins/nucleic acids is that
glycans are not synthesized using a template. Lots of enzymes for this purpose!!

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Polysaccharides:
As with protein and nucleic acids, the primary structure of polysaccharides is defined by the monomer
sequence
Homopolysaccharides = composed of the same monomer
Heteropolysaccharides = composed of 2 or more monomers

Even the most complicated of heteropolysaccharides are usually composed of no more than 2 or 3
monomers
Where does the functional diversity of polysaccharides come from?
1. There are a lot of different monomers available (biochemical modifications of sugars are common, slide
8).
2. Uniquely to polysaccharides, they are not prepared on a template, but rather their length and structures
(linear versus branched) are determined by the enzymes that synthesize them.
To introduce the general concepts of polysaccharides, we’ll discuss an example from each of the storage,
structural, and information-encoding functions of glycans.

Structural Information-encoding
Storage

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Storage Polysaccharides – Glucose Sources:

Storage homopolysaccharides are found in both animals (glycogen) and plants (amylose and amylopectin)
The differences are that amylose is linear and amylopectin is highly branched, and
glycogen is chemically similar to amylopectin except with more branching and higher molecular weight.
These glycans are central energy storage molecules that reduce monosaccharide solubility (limit diffusion)
and can be degraded to release b-D-glucose on demand. Branching occurs at a(16) linkages
between adjacent a-D-glucose residues.
Enzymes that release glucose from
glycogen do so from the non-
reducing end, which is one reason
why glycogen is highly branched Linear portions are
a(14) linkages
between adjacent a-
D-glucose residues.

Maintains glycan
size & allows rapid
mobilization of
glucose from Branching occurs every
multiple non- 10-12 residues in
reducing ends amylopectin, but every 8
simultaneously. residues in glycogen

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Structural Polysaccharides -Glycosaminoglycans:

Glycosaminoglycans are heteropolysaccharides derived from repeating disaccharide units where one of
the monosaccharides is N-acetyl-galactosamine or N-acetylglucosamine, or a derivative, and the other is
a uronic acid (C6 oxidation product).
*

Uronic Acid Glycosamine

D-glucuronic acid or N-acetylglucosamine or
L-iduronic acid N-acetylgalactosamine
*
*
*Sulfation at these positions is also common

Glycosaminoglycans make the “glue” that holds tissue

together: they can be found as soluble chains, or linked to
protein (proteoglycan) or lipids (glycolipid)

They are anions and they interact favorably with (protein)

cations. Example: Heparin as anticoagulant binder of
antiprothrombin III

They favorably H-bond to water, regulating the osmotic

pressure of tissues (gel-forming polysaccharides). Example:
Hyaluronic acid as lubricant in joints.

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Information-Encoding Polysaccharides –Blood Group Antigens:

Small heteropolysaccharides present on the surface of erythrocytes identify blood types in humans – they
encode important information about the compatibility of blood with an individual
The glycosylation of the lipid or protein
Humans with A anchor (R) occurs through N-
glycosyltransferase add an acetylgalactosamine to a hydroxyl group (O-
additional N- linkage) on R O-linkage
acetylgalactosamine to the
galactose residue present
in the non-antigenic Type O
polysaccharide

Humans with B
glycosyltransferase add an
additional galactose to the
galactose residue present in
the non-antigenic Type O
polysaccharide
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Information-Encoding Polysaccharides –Blood Group Antigens:

Small heteropolysaccharides present on the surface of erythrocytes identify blood types in humans – they
encode important information about the compatibility of blood with an individual

Antigenic: Antibodies can be produced

to specifically recognize and bind to
this polysaccharide

Nonantigenic: Antibodies cannot be

produced for this polysaccharide.

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Lipids:
Lipids are unique among biochemical building blocks: they form key cell structures through
non-covalent interactions as opposed to the covalent primary structures of proteins, nucleic
acids, and polysaccharides.

Amphiphilic

Self-assembly is driven by:

1. Hydrophobic effect (DS>0) Lipid structure determines the results of
2. Van der Waal’s interactions between self-assembly (micelle vs. bilayer)
hydrocarbon tails (DH<0)
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Structure of Lipids – Fatty Acids:

Fatty acids are the simplest lipids, and an important component of higher lipid structures
Octadecanoic Acid cis-9-Octadecenoic Acid

Most naturally
occurring unsaturated
fatty acids are cis
Polar Acid rather than trans,
(pKa≈4.5) Non-polar Hydrocarbon
b w-9 double resulting in a critical
w bond kink in the
1 18
a Saturated (max. number of H atoms) hydrocarbon
Unsaturated (≥1 double bond)

The hydrocarbon bonds have a large degree of conformational flexibility, making the fatty acids highly
dynamic –this imparts fluidity to the self-assembly structures that they form.
Most naturally occurring fatty
acids contain an even number
Total C# Total C=C# of C, due to formation through
sequential addition of ethyl
precursors.

Melting temperature increases

with the degree of VDW
C=C configuration C# at beginning of double bond interactions, and with close
packing ability of the
hydrocarbon chains.

Polyunsaturated fatty acids (PUFA)

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Structure of Lipids cont’d…:

Triacylglycerides:
Fatty acids are esterified with glycerol to form triacylglycerol for long term energy storage.
Glycerol Fatty Acid Triacylglyceride
If R1=R2=R3, then it is a simple fat

If R1≠ R2 (etc.), then it is a complex fat

In addition to energy storage, triacylglycerides allow for heat production in brown adipose tissue, as well as
insulation (fat cells in the skin).

Waxes:
The esterification of long chain fatty acids with a fatty alcohol results in a very weak amphiphile
that is highly hydrophobic.

They often serve as water-repellants in bird feathers or on coatings of

leaves.

Additionally, their long chain hydrocarbons provide very firm materials

which are use for the construction of large structures by some
organisms (e.g. beeswax)
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Lipids of Biological Membranes:

Lipid molecular structure directly influences the self-assembled structures that are formed in
physiological media.

A single hydrocarbon chain on A double hydrocarbon chain on

a polar head group yields a a polar head group yields a
cone-shaped van der Waal cylinder-shaped van der Waal
envelope. ~60 Å envelope.

The closest-packing The closest-packing

conformation of cones is a conformation of cylinders is in
sphere, leading to micelle parallel sheets, leading to
formation in water. bilayer (or membrane)
formation in water.
In reality, the lipids reside somewhere on a continuum between these two conformations, cylindrical enough
to form a bilayer, but with some conical nature to provide membrane curvature.

There are four categories of membrane lipids that

can be characterized based on their varied head-
group chemistry (why the headgroup?):

Glycerophospholipids
Sphingolipids
Glycosphingolipids
Glycoglycerolipids
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Glycerophospholipids:
These are the major class of naturally occurring phospholipids – lipids with 2 fatty acid chains
and one phosphate group conjugated to a glycerol molecule

Assuming A≠B, now where

Where is the is the stereocentre of
stereocentre of glycerol?
glycerol? *
Glycerol is prochiral: it has
no stereochemistry until
asymmetrically derivatized

Phospho Hydrocarbon
head group Tail The hydrocarbon composition
of R1 and R2 are also highly
variable, bearing different
chain lengths and varying
degrees and locations of
unsaturation.

This “combinatorial” nature of

glycerophospholipids allows
the fine tuning of cell
membrane properties and
functions (fluidity and
headgroup interactions…)
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Glycoglycerolipids, Sphingolipids & Glycosphingolipids:

Glycerophospholipid Sphingolipid
Major constituents
of the cell
membrane
If R2=H, ceramide

Important for brain

and nerve function
Glycerol Sphingosine

Glycoglycerolipid Glycosphingolipid
Major components
of plant and archaea
membranes

ABO blood group

antigens; brain and
nerve function
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Membrane Asymmetry:
Lipid distribution is asymmetrical and
derives from leaflet synthesis and
transport from smooth endoplasmic
reticulum.

Results in the differential distribution of

charge (neutral to extracellular space
and anionic to intracellular space), and
head group reactivity
Effects glycosylation
distribution, transmembrane protein
distribution and orientation, and
membrane transport activities.

Membrane Fluidity:

Differentially-labeled
membrane protein
diffusion over time
(t<60 min).
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Cholesterol and Membrane Fluidity:

Cell function is critically dependent on local environments of membrane fluidity and rigidity.
Lateral Diffusion Transverse Diffusion
Individual lipid molecules The movement of
are highly mobile in the individual lipid molecules
plane of the lipid bilayer transversely between
(within the same leaflet), membrane leaflets is very
diffusing as fast as 1 mm/s. rare and, due to
This mobility thermodynamic
makes the bilayer a 2-D constraints, are often
fluid enzyme-catalyzed by
flippases

Cholesterol

In addition to glycerol and sphingosine-derived

lipids, cholesterol is a key lipid component
comprising up to 25% of the cell membrane.

Cholesterol breaks up the oil-like nature of the

hydrophobic core to rigidify the membrane
leaflets.
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Building Blocks of Biochemistry:

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