Molecules of Living Systems (Part-2)

INTERACTIONS BETWEEN BIOMOLECULES ARE STEREOSPECIFIC

Stereospecificity: ability to distinguish between stereoisomers.

Exhibited by enzymes and other proteins.

Important characteristic feature on which the molecular logic of

living cells has been developed.

E.g., food: largely made of molecules of one mirror-image form.

If food was made of molecules with the unnatural mirror-image
form, we would starve because the enzymes in our bodies are
chiral and have evolved in such a way that they preferentially
recognize the natural mirror-image form of their substrates.
INTERACTIONS BETWEEN BIOMOLECULES ARE STEREOSPECIFIC

A diagram
showing how only
one amino acid in
a pair of
enantiomers can
interact in an
optimal way with
a hypothetical
asymmetric
binding site (e.g.,
in an enzyme).
MOLECULAR SHAPE AND THE SENSE OF SMELL
Odor of a molecule is determined more by its shape than by the
presence of a particular functional group.

E.g., hexachloroethane (Cl3CCCl3) and cyclooctane (C8H16) have no

obvious structural similarities, but they both have a camphor-like
odor, a fact attributed to their similar spherical shape.

Each molecule binds to spherically shaped olfactory receptors

present on the nerve endings in the nasal passage, resulting in
similar odors.

cyclooctane (C8H16)
hexachloroethane (Cl3CCCl3)
ENANTIOMERS AND THE SENSE OF SMELL

Some enantiomers interact with chiral smell receptors, and hence

have different odors. For example, (S)-carvone is responsible for
the odor of caraway, whereas (R)-carvone is responsible for the
odor of spearmint.
STEREOISOMERS DISTINGUISHABLE BY TASTE

Aspartame, the artificial sweetener sold under the trade name

NutraSweet, is easily distinguishable by taste receptors from its
bitter-tasting stereoisomer, although the two differ only in the
configuration at one of the two chiral carbon atoms.
CHIRAL DRUGS
Action of drugs on human has been found to be highly dependent
on the stereochemistry of the asymmetric center of the chiral drug
molecules.
E.g., the enantiomer of the pain killer Darvon acts as a cough
suppressant (Novrad).
VERSATILITY OF BIOMOLECULES OWES LARGELY TO THEIR
FUNCTIONAL GROUPS

A large variety of groups of atoms, called functional groups, are

attached to the carbon skeletons of biomolecules and impart
specific chemical properties to the molecule.

This indicates that the bonding versatility of carbon was possibly

the major factor in the selection of carbon compounds (organic
compounds) as the molecular repertoire of cells during the
origin and evolution of living systems.

No other chemical element has been found to form molecules

of such versatility in terms of sizes and shapes or with such a
variety of functional groups (and hence chemical properties).
COMMON BIOMOLECULAR FUNCTIONAL GROUPS
Typical examples functional groups found in biomolecules are
shown below.

[All groups are shown in their uncharged (nonionized) form. We use R to represent “any
substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing
moiety. When two or more substituents are shown in a molecule, we designate them R1, R2,
and so forth.]
COMMON BIOMOLECULAR FUNCTIONAL GROUPS
Typical examples functional groups found in biomolecules are
shown below.

[All groups are shown in their uncharged (nonionized) form. We use R to represent “any
substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing
moiety. When two or more substituents are shown in a molecule, we designate them R1, R2,
and so forth.]
COMMON BIOMOLECULAR FUNCTIONAL GROUPS
Typical examples functional groups found in biomolecules are
shown below.

[All groups are shown in their uncharged (nonionized) form. We use R to represent “any
substituent.” It may be as simple as a hydrogen atom, but typically it is a carbon-containing
moiety. When two or more substituents are shown in a molecule, we designate them R1, R2,
and so forth.]
BIOMOLECULES MAY CONTAIN MULTIPLE DIFFERENT
FUNCTIONAL GROUPS
Many biomolecules are polyfunctional, containing two or more
different functional groups, each with its own chemical
characteristics and reactivity.

The chemical “personality” of such compounds, is determined by

the chemistry of the functional groups in combination and their
stereochemistry.

(an amino acid found in proteins) (a hormone)

BIOMOLECULES MAY CONTAIN MULTIPLE DIFFERENT
FUNCTIONAL GROUPS

(a carrier of acetyl groups in many enzymatic reactions)

CHEMICAL REACTIVITY OF BIOMOLECULES
The mechanisms of biochemical reactions could be deciphered from
the nature of the functional groups of the reactants.

Functional groups causes change in the electron distribution and the

geometry of neighboring atoms and thus results in the chemical
reactivity of the entire molecule.

Although a large number of different chemical reactions occur in a

typical cell, these reactions could be classified into a few general
types.

Almost all of the cellular chemical reactions are enzyme catalyzed.

This allows the reactions to happen in cellular conditions (pH,
temperature, ionic strength, etc) in very high efficiency, precision and
control.
CHEMICAL TRANSFORMATIONS WITHIN CELLS: SIX GENERAL TYPES
Most of the cellular reactions fall into one of six general categories:

(1) oxidation-reductions or redox reactions,

(2) cleavage and formation of carbon–carbon bonds,

(3) intramolecular rearrangements,

(4) group transfers,

(5) condensation reactions in which monomeric subunits are joined

to form biopolymers, and

(6) Depolymerization of biopolymers.

Reactions within each general category usually occur by similar

mechanisms.
ELECTRON TRANSFER: AN ESSENTIAL FEATURE OF
REDOX REACTIONS
In many biological redox reactions, a molecule loses two electrons
and two hydrogen ions (i.e., the equivalent of two hydrogen atoms).
These reactions are commonly called dehydrogenations and the
enzymes that catalyze them are called dehydrogenases

E.g., oxidation of lactate to pyruvate, catalyzed by lactate

dehydrogenase: two electrons and two hydrogen ions are removed
from the C-2 of lactate, whose alcohol group is oxidized to a ketone in
the product pyruvate. The electrons are transferred to a cofactor
called nicotinamide adenine dinucleotide. This reaction is fully
reversible; pyruvate can be reduced by electrons from the cofactor.
ELECTRON TRANSFER: AN ESSENTIAL FEATURE OF
REDOX REACTIONS

In some biological oxidations, a carbon atom gets covalently bonded

to an oxygen atom.

The enzymes that catalyze these oxidations are generally called

oxidases or, if the oxygen atom is derived from molecular oxygen (O2),
oxygenases.

Every oxidation is always accompanied by a reduction, in which an

electron acceptor acquires the electrons removed by oxidation.
ELECTRON TRANSFER: AN ESSENTIAL FEATURE OF
REDOX REACTIONS

Most living cells obtain the energy needed to run cellular processes by
oxidization of metabolic fuels such as carbohydrate or fat.

Most of the cellular catabolic (energy-yielding) pathways are

sequences of oxidative reactions that transfer electrons from fuel
molecules through a series of electron carriers and finally to
molecular oxygen.

Due to the high affinity of O2 for electrons the overall electron-

transfer process is highly exergonic, and the energy obtained drives
ATP synthesis — the ultimate purpose of catabolism.
CLEAVAGE AND FORMATION OF CARBON–CARBON BONDS
A covalent bond can be broken in two general ways, homolytic and
heterolytic. In homolytic cleavage (biologically
rare), each atom leaves the bond
as a radical, carrying one of the
two electrons (now unpaired) that
held the bonded atoms together.

In heterolytic cleavage
(biologically much more
common), one atom keeps
both bonding electrons
(forming an anion), leaving
[Carbanions and carbocations are generally unstable – the other atom one
their formation and stabilization are facilitated by the electron short (a cation).
presence of neighboring functional groups containing
respectively electron pushing (e.g., alkyl groups) or
electron withdrawing (e.g., OH, NH2) gropups that can
alter the electronic structure of adjacent carbon atoms.]
CLEAVAGE AND FORMATION OF CARBON–CARBON BONDS:
NUCLEOPHILIC SUBSTITUTION REACTIONS

Many biochemical reactions involve interactions between nucleophiles,

functional groups rich in electrons and capable of donating them, and
electrophiles, electron-deficient functional groups that seek electrons.

Nucleophiles combine with, and give up electrons to, electrophiles.

Electrophile
A nucleophilic substitution
reaction. An electron-rich
nucleophile (Z) attacks an
electron-poor center or
electrophile (a carbon atom,
here) and displaces a poorer
nucleophile (W), which is called
the leaving group.
CLEAVAGE AND FORMATION
OF CARBON–CARBON BONDS:
NUCLEOPHILIC SUBSTITUTION
REACTIONS

Common nucleophiles
and electrophiles
involved in biochemical
reactions.

A carbon atom can

act as either a
nucleophile or an
electrophile,
depending on the
context of its
neighboring
functional groups.
CLEAVAGE AND FORMATION OF CARBON–CARBON BONDS: SOME
COMMON REACTIONS

E.g., the aldolase reaction, that converts a six-carbon compound to

two three-carbon compounds in glycolysis, is an aldol condensation in
reverse.

The carbanion is stabilized by

delocalization of the electrons into
the adjacent carbonyl group.
CLEAVAGE AND FORMATION OF CARBON–CARBON BONDS: SOME
COMMON REACTIONS

E.g., synthesis of citrate in the citric acid cycle.

The carbanion is stabilized by

delocalization of the electrons into
the adjacent carbonyl group.
CLEAVAGE AND FORMATION OF CARBON–CARBON BONDS: SOME
COMMON REACTIONS

E.g., the acetoacetate decarboxylase reaction that occurs in the

formation of ketone bodies during fatty acid catabolism.

The carbanion is stabilized by

delocalization of the electrons into
the adjacent carbonyl group.
 INTRAMOLECULAR REARRANGEMENTS: ELECTRON TRANSFER
WITHIN A MOLECULE
In intramolecular rearrangement, redistribution of electronswithin the
molecule itself results in isomerization, transposition of double bonds,
and cis-trans rearrangements of double bonds.

E.g., the formation of fructose 6-phosphate from glucose 6-phosphate

during sugar metabolism.

In this reaction, C-1 is reduced (from aldehyde to alcohol) and C-2 is

oxidized (from alcohol to ketone). Effectively, the carbonyl and the
alcohol group rearrange their mutual positions between C-1 and C-2.
GROUP TRANSFER REACTIONS:
ACTIVATION OF METABOLIC INTERMEDIATES
A common theme in metabolism is the attachment of a good leaving
group to a metabolic intermediate to “activate” the intermediate for
the following reaction.

Inorganic orthophosphate (Pi) and inorganic pyrophosphate (PPi) are

among the better and most common leaving groups in nucleophilic
substitution reactions of metabolic pathways.

Nucleophilic substitution is made more favorable by the attachment

of a phosphoryl group (—PO32-) to an otherwise poor leaving group
such as —OH.

As oxygen is more electronegative than phosphorus, the sharing of

electrons is unequal. The central phosphorus bears a partial positive
charge and can therefore act as an electrophile.
GROUP TRANSFER REACTIONS:
ACTIVATION OF METABOLIC INTERMEDIATES
In many metabolic reactions, a phosphoryl group (—PO32-) is
transferred from ATP to an alcohol forming a phosphate ester.

Hexokinase

When a nucleophile (in this case, the —OH on C-6 of glucose) attacks
ATP, it displaces ADP (leaving group).
The large family of enzymes that catalyze phosphoryl group transfers with ATP as donor are
called kinases (Greek kinein, “to move”).
Thiols and thioesters are also similarly used in many metabolic reactions, e.g., in lipid
metabolism.
CONDENSATIONS: FORMATION OF BIOPOLYMERS
The monomeric subunits that constitute biopolymers, such as
proteins, nucleic acids, and polysaccharides, are joined by
nucleophilic displacement reactions that replace a good leaving
group.
E.g., the joining of two amino acid molecules to form a dipeptide.

Simply, the removal of

the elements of water
from two molecules of
the amino acid glycine
apparently might a
peptide bond, but
because —OH is not a
good leaving group,
this reaction is
unfavorable.
CONDENSATIONS: FORMATION OF BIOPOLYMERS
Cells solve this problem by first attaching a better leaving group, a
small RNA molecule (transfer RNA, about 75 nucleotides long), in
ester linkage to the α-carboxyl group of the amino acid. This activates
the carboxyl group for condensation with the α-amino group of
another amino acid.

Catalyzed by rRNA within

the ribosome

Similar strategies are

employed in the
biosynthesis of
nucleic acids and
polysaccharides.
HYDROLYSIS: DEPOLYMERIZATION OF BIOPOLYMERS
Macromolecules can be broken down by hydrolysis reactions, in
which H2O is the attacking nucleophile, displacing a monomeric
subunit or a smaller polymer fragment. Enzymes that catalyze
hydrolysis of biopolymers (hydrolases) are essential in the digestive
process and serve also to regulate the level of such critical
macromolecules asproteins and messenger RNA.
The hydrolysis of a
peptide bond
(shown here in a
polypeptide) is
essentially the
reverse of the
reaction in the
previous figure:
H2O makes a
nucleophilic attack
on the carbonyl
carbon, displacing
the nitrogen of the
α-amino group.