Download Introduction—Proximity Effects and Molecular Adaptation

CHAPTER
1
Introduction—Proximity Effects and
Molecular Adaptation
1.1 INTRODUCTION TO BIOORGANIC, BIOINORGANIC AND
SUPRAMOLECULAR CHEMISTRY
Organic chemistry generally deals with the chemistry of carbon compounds regardless of their
origin. Biochemistry, on the other hand, deals only with the carbon chemistry of life.
Biochemistry aims to explain biological form and function in chemical terms. Biomolecules
are compounds of carbon with different functional groups, thus the chemistry of living organism
revolves around carbon. Carbon accounts for more than half of the dry weight of cells. The five
other abundant elements are hydrogen, oxygen, nitrogen, phosphorus and sulfur and these
five taken together make up more than 90% of the mass of most cells. Significantly, only about
30 naturally occurring elements are essential to the organism and have relatively low atomic
numbers and only few have atomic numbers higher than that of selenium (34). The other
important elements in cells are: Ca, K, Na, Cl, Mg, Fe, Cu, Co, I, Zn, F, Mo and Se.
The general principles of organic chemistry provide strong foundations for understanding biochemistry. One however, may know that biochemistry deals exclusively with the reactions which occur in the living system in the aqueous medium.
What is Bioorganic Chemistry/Elimination Reactions as an Example
The understanding of the biochemical processes with the application of the tools
of organic chemistry e.g., reaction mechanism, catalysis etc. is termed bioorganic
chemistry. As an example consider elimination reactions. The common mechanism
for an elimination reaction is the bimolecular E2 reaction where the removal of
one group occurs at the same time as the other group is leaving (Scheme 1.1). In
Base:
X
Base H
H
+
+
–
X
SCHEME 1.1
another E1 (unimolecular) mechanism the heteroatomic anion leaves first to give
a carbocation intermediate and subsequently β hydrogen is lost (Scheme 1.1a). In
some situations it is possible that the proton may leave first to instead give a carbanion
+
+
H
X
H
Base:
SCHEME 1.1a
1
Base H
+
–
X
2
Bioorganic, Bioinorganic and Supramolecular Chemistry
in the E1cB mechanism (Scheme 1.1b). E1cB stands for unimolecular elimination
conjugate base reaction since the conjugate base of the substrate is involved as the
+
:
–
H
Base:
BH
+
–
X
X
X
SCHEME 1.1b
reactive intermediate. E1cB mechanism is favoured by those substrates which
have an acidic hydrogen i.e., the carbanion formed is stable and the leaving group
is a poor leaving group. A good example is during the aldol condensation between
two molecules of acetaldehyde. Under the normal basic conditions, the initial
product aldol, eliminates water to give crotonaldehyde (Scheme 1.1c). Note that
carbanion (II, Scheme 1.1c) is stable since a good carbanion stabilising aldehyde
–
group which is – M type is present, and also OH a strong base is a poor leaving
group.
O
OH
OH
2CH3—C—H
O
O
–
CH3—CH—CH2—C—H
Acetaldehyde
CH3—CH
Aldol
3-hydroxybutanal
2-Butenal
Product of aldol condensation
OH
O
: :
O
:
CH3—CH—CH—C—H
–
(II)
H
–
:OH
: :
–
– : OH
OH
CH3—CH—CH—C—H
CH—C—H
(I)
Dehydration via an E1cB mechanism
SCHEME 1.1c
Recall that normally water is eliminated under acidic conditions in which the
hydroxy group is protonated to give O–H2+ which would subsequently give rise to a
far better leaving group, H2O.
Elimination reactions occur in living organisms as well. An example is the
conversion of 2-phosphoglycerate to phosphoenolpyruvate during the metabolism
of glucose (Scheme 1.1d). This elimination is an E1cB mechanism which is catalysed
enzyme
O—PO3
CH2
C—CO2
B:
2+
2–
OH
–
H
Mg
Fast
2–
OH
O—PO3
CH2
C—CO2
–
–
:
2+
Mg
2–
O—PO3
Slow
CH2
C
–
CO2
Phosphoenolpyruvate
enzyme —B—H
+
2-Phosphoglycerate
SCHEME 1.1d
Introduction—Proximity Effects and Molecular Adaptation
3
by the enzyme enolase. The enzyme supplies a base to remove the acidic proton to
form a carbanion in the first step. In addition, a Mg2+ cation in the enzyme acts as
a Lewis acid and bonds to hydroxy group, making it a better leaving group.
Charles Pedersen, a chemist at DuPont, first prepared and studied the crown ethers
in 1967, demonstrating that they bind alkali metal ions. This achievement was
recognized by his sharing the 1987 Nobel Prize in chemistry with Jean-Marie
Lehn and Donald Cram.
This provides an example of host-guest relationship, the crown ether is the host;
the cation is the guest. This kind of relationship helps in designing better reagents
e.g, purple benzene for oxidation purposes, and understanding wide range of interactions, the one between an enzyme and its substrate.
A new field has therefore, emerged. Cram calls it ‘‘host guest’’ chemistry while
Lehn calls it supramolecular chemistry. This is the chemistry of noncovalent
intermolecular forces that bind two or more molecules leading to supramolecules.
Molecular biology is generally more associated with organic chemistry, however,
inorganic elements and metal ions are of prime importance to biological processes
e.g, the role of Fe in hemoglobin. Among the recent discoveries mention may be
made of zinc fingers which occur in many proteins and are involed in regulation
of transcriptions.
1.2 BIOLOGICAL SCIENCES—ORGANIC CHEMISTRY AND BIOCHEMISTRY
It is hard to set a date for the beginning of biochemistry, since this subject is a mix of biological
sciences and particularly organic chemistry. The breakthrough in enzyme research and
therefore, the study of biochemistry was made in 1877 by E. Buchner when an enzyme was
extracted from yeast cells in crude form which was used to ferment sugar. The twentieth
century witnessed several major discoveries and developments in biochemistry. Around 1926
the protein nature of enzymes was established and the first enzyme (urease) was purified and
crystallized. Structure and function of many enzymes and coenzymes and DNA and RNA was
established. The twentieth century saw the major developments/discoveries in biochemistry
as evidenced by the award of several Nobel Prizes. Some of the more important discoveries are:
• Role of ATP in energy-yielding and energy requiring processes (1940, F. Lipmann).
• Role of organic molecules e.g., vitamins as components of some enzymes and citric
acid cycle (1935–37, Kuhn and Kreb).
• Importance of coenzymes in biological reactions and discovery of Calvin cycle in
photosynthesis (1947–48).
• Metabolic pathways (1955).
• Structure of DNA (Watson and Crick) and amino acid sequence of proteins (Sanger)
(1953).
• X-ray analysis determining a three dimensional structure of the sperm whale
myoglobin (J. Kendrew 1960).
• Genetic code (1965, Nirenberg Khorana and Holley).
• Biochemistry of immune systems (1980, Snell, Benacerraf and Dausset). Development
of methods for joining together two unrelated DNA molecules.
• Discovery of a neural growth factor which stimulates the growth of nerve cells (1986,
Rita Levi-Montalcini and Stanley Cohen).
• Biochemistry of body’s immune defence (1987, Susuma Tonegawa).
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Bioorganic, Bioinorganic and Supramolecular Chemistry
The science of biochemistry continues to grow tremendously and research in new drugs
which can block nucleic acid synthesis in cancer cells without effecting the normal cells is
outstanding (1988) and the determination of the three dimensional structure of the photosynthetic reaction centre is equally outstanding.
1.3 BASIC CONSIDERATIONS—CHEMICAL BACKGROUND
(A) Some Functional Groups of Biomolecules
Generally biomolecules may be regarded as derivatives of hydrocarbons, where some of the
hydrogen atoms are replaced by a variety of functional groups. This gives different families of
bioorganic compounds or in short biomolecules. The properties of a biomolecule is associated
with the chemistry of the functional groups and stereochemical organization. Some of the
more important functional groups are given (Scheme 1.2).
Functional group
Name
General formula
Structure
Type of
compound
Examples of
biomolecule(s)
Hydroxyl
—OH
R—OH
Alcohol
Glycerol, ethanol
Aldehyde
O
⏐⏐
— C ⎯H
O
⏐⏐
R— C ⎯H
Aldehyde
Glyceraldehyde, glucose
Keto
O
⏐⏐
—C⎯
O
⏐⏐
R1— C ⎯ R2
Ketone
Fructose, sedoheptulose
Carboxyl
O
⏐⏐
— C ⎯ OH
O
⏐⏐
R— C ⎯ OH
Carboxylic acid
Acetic acid, palmitic acid
Amino
—NH2
R—NH2
Amino acid
Alanine, serine
Imino
H
⏐
—N⎯
H
⏐
R— N ⎯
lmino acid
Proline, hydroxyproline
Sulfhydryl
—SH
R—SH
Thiol
Cysteine, coenzyme A
Ether
—O—
R1—O—R 2
Ether
Thromboxane A2
Ester
O
⏐⏐
— C ⎯ O ⎯ R1
O
⏐⏐
R2— C ⎯ O ⎯ R1
Ester
Cholesterol ester
O
⏐⏐
R
— C —N 1
R2
O
⏐⏐
R
R3— C — N 1
R2
Amide
N-Acetylglucosamine
Amido
Some common functional groups of biomolecules
SCHEME 1.2
Some other functional groups containing phosphorus along with nitrogen sulphur and
oxygen are presented (Scheme 1.3).
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Introduction—Proximity Effects and Molecular Adaptation
Biomolecules also contain several heterocyclic as well as homocyclic rings as given
(Scheme 1.4). Of these ring systems e.g., phenyl ring derived from benzene occurs in the amino
acids (phenylalanine and tyrosine, while indole is a part of amino acid tryptophan, Table 1.1).
Phenanthrene and cyclopentane form the backbone of steroids e.g. cholesterol. Furan is the
ring structure found in pentoses. Pyrrole is the basic unit of porphyrins found in several
biomolecules (heme) while pyrolidine is the ring present in the amino acid, proline (Table 1.1).
Thiophen ring is a part of the vitamin biotin. The amino acid histidine contains the ring
structure of imidazole (Table 1.1).
H
H
H
R—N
R—C—N
H
H
R—N—C—N
H
O
R——C
HN
N
C
H
N
H
H
Amino
Amido
R—S—H
1
Gvanidino
R —S—S—R
2
1
R —C—S—R
Imidazole
2
1
R —C—O—R
O
Sulfhhydrol
–
Disulfide
–
O
R—O—P—OH
O
HO—P—OH
O
Phosphoryl
Phosphoric acid
O
Ester
–
–
O
1
R —O—P—O—P—O—R
O
2
O
Thioester
–
O
CH
O
Phosphoanhydride
O
2
R—C—O—P—OH
O
O
Acylphosphate
(Mixed anhydridecarboxylic acid and
phosphoric acid)
Some more important functional groups present in biomolecules
SCHEME 1.3
Pyran structure is found in hexoses. Pyridine nucleus is a part of the vitamins-niacin
and pyridoxine. Pyrimidines (cytosine, thymine) and purines (adenine, guanine) are the constituents of nucleotides and nucleic acids. Indole ring is present in the amino acid tryptophan
(Table 1.1). Purine and indole are examples of fused heterocyclic rings.
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Bioorganic, Bioinorganic and Supramolecular Chemistry
N
O
N
Furan
Pyrrole
S
N
Thiophene
Imidazole
H
H
NH2
N
N
N
O
N
N
N
Pyran
Pyridine
Pyrimidine
N
N
H
Purine
N
N
H
H
Indole
N
N
Adenine
(A purine base)
Heterocyclic rings
Homocyclic and heterocyclic rings generally found in biomolecules
SCHEME 1.4
The Five Bases and Two 5-Carbon Sugars Present in RNA and DNA
The five bases present in RNA and DNA are derivatives of pyrimidine and purine
(Scheme 1.4) and are called adenine, cytosine, uracil, guanine and thymine. Three
of these (cytosine, adenine and guanine) are common to both kinds of nucleic acids
and the other two (thymine and uracil) differ only in the presence or absence of a
methyl group (see, Scheme 1.27a).
The structures of two five carbon sugars present in RNA and DNA are given in
Scheme 1.4a. D-glucose is another important six carbon sugar involved in
biosystems.
CH2OH
5
O
HOCH2
H
HOCH2
H
O
H
1
4
H
O
H
3
OH
H OH
H
H
H OH
OH
H
HO
H
H
OH
H
H
OH
OH
2
OH
a-D-Ribose
2-Deoxy-a-D-ribose
Five-carbon sugars
a-D-Glucose
A six-carbon sugar
SCHEME 1.4a
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Introduction—Proximity Effects and Molecular Adaptation
PROBLEM 1.1. The structure of a single biomolecule acetyl-coenzyme A, abbreviated as acetyl-CoA which is a carrier of acetyl groups in several enzymatic reactions is presented (Scheme 1.5). Name the component functional groups shown in
boxes.
Acetyl coenzyme A
SCHEME 1.5
ANSWER. (1) Adenine (ring A is imidazole); (2) phosphoanhydride; (3) amide;
(4) thioester.
PROBLEM 1.2. Write a short note on bioorganic chemistry. Write the structures
of imidazole, purine and pyrimidine.
PROBLEM 1.3. The structure of biotin (Vitamin H) is
given (Scheme 1.6). This vitamin serves as a carrier of
CO2 in carboxylation reactions. This vitamin is also
called anti egg white injury factor since it protects animals against the toxicity of raw egg white. Give the
structural features present in the vitamin.
ANSWER. It may be looked as a heterocyclic (sulphur
containing) monocarboxylic acid. One may also define
it as a cyclic derivative of urea (A) with a ring system
(B) related to thiophene. Broadly speaking the vitamin
is a fused ring system of imidazole and thiophene ring.
O
C
H—N
N—H
(A)
H—C
C—H
(B)
H2—C
C—(CH2)4—COOH
S
H
Biotin (Vitamin H)
SCHEME 1.6
8
Bioorganic, Bioinorganic and Supramolecular Chemistry
(B) Proteins and Amino Acids
Proteins are important biological macromolecules and these play a variety of roles in the
functions of living systems. These control cell growth and differentiation and recognize foreign
substances. The monomeric subunits in proteins are a variety of amino acids and 20 of these
with their structures, and abbreviations are given (Table 1.1). The structures of shaded amino
acids will find more often reference in this book.
Table 1.1 Common amino acids
Name
Abbreviation
Structure
Non polar R group
Alanine
Ala or A
CH3— CH ⎯ COOH
⏐
NH2
Valine
Val or V
CH3— CH ⎯ CH ⎯ COOH
⏐
⏐
CH3 NH2
Leucine
Leu or L
CH3— CH ⎯ CH2— CH ⎯ COOH
⏐
⏐
NH2
CH 3
Isoleucine
Ile or I
CH3—CH2— CH ⎯ CH ⎯ COOH
⏐
⏐
CH3 NH2
Phenylalanine
Phe or F
Tryptophan
Trp or W
CH2— CH ⎯ COOH
⏐
NH2
N
CH2— CH ⎯ COOH
⏐
NH2
H
Methionine
Met or M
Proline
Pro or P
CH3—S—CH2CH2— CH ⎯ COOH
⏐
NH2
N
H
COOH
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Introduction—Proximity Effects and Molecular Adaptation
Polar but neutral R group
Serine
Ser or S
HO—CH2— CH ⎯ COOH
⏐
NH2
Threonine
Thr or T
CH3— CH ⎯ CH ⎯ COOH
⏐
⏐
OH NH2
Tyrosine
Tyr or Y
CH2— CH ⎯ COOH
⏐
NH2
HO
Cysteine
Cys or C
HS—CH2— CH ⎯ COOH
⏐
NH2
Asparagine
Asn or N
NH2— C —CH2— CH ⎯ COOH
⏐
⏐⏐
NH2
O
Glutamine
Gin or Q
NH2— C —CH2CH2— CH ⎯ COOH
⏐
⏐⏐
NH2
O
Glycine
Gly or G
H— CH ⎯ COOH
⏐
NH2
Glutamic acid
Glu or E
HO— C —CH2CH2— CH ⎯ COOH
⏐⏐
⏐
O
NH2
Aspartic acid
Asp or D
HO— C —CH2— CH ⎯ COOH
⏐⏐
⏐
O
NH2
Lysine
Lys or K
NH2—CH2CH2CH2CH2— CH ⎯ COOH
⏐
NH2
Arginine
Arg or R
Histidine
His or H
Acidic R group
Basic R group
NH2— C ⎯ NH—CH2CH2CH2— CH ⎯ COOH
⏐⏐
⏐
NH
NH2
N
CH2— CH ⎯ COOH
⏐
NH2
N
H
10
Bioorganic, Bioinorganic and Supramolecular Chemistry
Proteins are the most abundant macromolecules of the cell by which genetic information
is expressed. The two types of nucleic acids i.e., DNA and RNA serve as repositories and
transmitters of genetic information. The genes control the protein synthesis (amino acid
sequence) via the involvement of RNA (Scheme 1.7).
DNA
RNA
Protein
The genes control the protein synthesis through the mediation of RNA
SCHEME 1.7
(C) Some Properties of Amino Acids—The Building Blocks of Proteins/Enzymes
(I) Non polar and polar amino acids and their acidity and basicity
• Nonpolar amino acids. These amino acids (Table 1.1) contain a side chain which is
nonpolar like alkyl groups, aromatic rings or other nonpolar groups. Alanine is the amino acid
with a methyl side chain and valine has an isopropyl group, leucine an isobutyl group and
isoleucine a secondary butyl group.
Phenylalanine looks like alanine with a phenyl ring replacing one of the hydrogen atoms
of the methyl group. The aromatic ring of the other amino acid, tryptophan, is fused to a
second ring that contains nitrogen. This two-ring system is called indole, and it may be helpful
to picture tryptophan as alanine that has an indole replacing one of the methyl hydrogen
atoms.
Methionine is a sulphur-containing amino acid and is a thioether. Like ethers, thioethers
are relatively nonpolar. The amino acid proline has a ring of five atoms that includes the αcarbon atom and the α-nitrogen atom of the amino group. One end of the side chain is bonded
to the α-carbon atom, and the other end to the nitrogen atom of the α-amino group. This ring
structure makes proline unique among the amino acids, and it thus has a special role in protein structure.
• Polar amino acids. In these amino acids the side chain has one or more polar groups.
These amino acids can be placed into three sub groups:
(i) Neutral polar amino acids. In the amino acids of this group the side chains are
polar, but not ionic. Two amino acid side chains contain alcohol groups. Serine is an HOsubstituted alanine, and threonine has a branched ethanol substituent. There are also two
sulphur-containing amino acids; cysteine is an HS-substituted alanine, and methionine has a
2-methylthioethyl substituent.
(ii) Acidic amino acids. There are two acidic amino acids (amino acids with two
carboxylic acid groups): aspartic acid, which is a carboxy-substituted alanine; and glutamic
acid, which has one more methylene group than aspartic acid. Two amino acids are amides of
the acidic amino acids: asparagine, which is the amide of aspartic acid; and glutamine, is the
amide of glutamic acid.
(iii) Basic amino acids. Polar amino acids contain one or more nitrogen atoms that
have an unshared pair of electrons; they are Lewis bases. Lysine has an amino group on the
end of a chain of four carbon atoms. Arginine has a side chain consisting of four carbon atoms