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CHEM1222 Chemistry for Pharmacy and Dentistry

CHEM1222 Chemistry for Pharmacy and Dentistry

Lecture 11 Molecules of life: Carbohydrates

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Macromolecules:

Carbohydrates – lecture overview

• Biological structures based on macromolecular assemblies including polymer molecules.

• What are carbohydrates? • Where do we find them and what do they do?

• In this module, examine the structure of these biomolecules then consider the thermodynamic explanations for their properties and selfassembly into macrostructures.

• Different classes o Structures

• Reactivity o Formation of glycosides o Reduction o Oxidation Blackman etal. 4th Edition Chapter 22 CHEM1222 – Chemistry for Pharmacy and Dentistry

Blackman Chapter 22

CHEM1222 – Chemistry for Pharmacy and Dentistry

What are carbohydrates?

Where do we find carbohydrates? Major biological functions of carbohydrates • Storage of chemical energy

• An important class of biological molecules

 glucose, starch, glycogen

• Originally defined as “hydrates of carbon”  Cn(H2O)m

• Structural carbohydrates

 many do not fit this general formula

 Cellulose (plants), chitin (crustaceans), connective tissues (animals)

• Chemically, carbohydrates are:

Other biological roles • Components of DNA and RNA

 polyhydroxyaldehydes or polyhydroxyketones  Therefore, carbohydrate chemistry is based on that of:  Hydroxyl (-OH) and carbonyl (C=O) groups (Ch. 18, 20)  Acetal groups (from reaction between OH and C=O groups) (Ch 20.3)

 D-ribose and 2-deoxy-D-ribose

• Cell surface and membrane recognition processes  blood typing, immunology

 Other functional groups may also be present (e.g. -NH2) CHEM1222 – Chemistry for Pharmacy and Dentistry

Blackman p. 1348 CHEM1222 – Chemistry for Pharmacy and Dentistry

Monosaccharides

Monosaccharide stereochemistry

• Monosaccharides contain one carbon chain  General formula: CnH2nOn (n is typically 3 – 9)

• Contain one carbonyl (C=O) group  Aldoses contain an aldehyde group  Ketoses contain a ketone group

• • • •

 Suffix “-ose” identifies a carbohydrate  Precursors “tri-, tetr-, pent-” etc indicate the number of carbon atoms in the main chain CHEM1222 – Chemistry for Pharmacy and Dentistry

Carbohydrates contain multiple chiral centres (*) Stereochemistry is crucial to their biological activity Each stereocentre can be described using R or S It is common with carbohydrates, to use the D/L system  Assigned by considering the configuration of the stereocentre furthest from the carbonyl group  Relative to the dextro- (d) and levo-rotatory (l) enantiomers of glyceraldehyde

Blackman p. 1349 CHEM1222 – Chemistry for Pharmacy and Dentistry

Blackman p. 1349

Monosaccharide stereochemistry

Monosaccharide stereochemistry

e.g. the aldotetroses

Carbohydrates are commonly drawn using Fischer Projection • 2D representation of 3D stereochemistry CHEM1222 – Chemistry for Pharmacy and Dentistry

Cyclic monosaccharides

• Name prefixes (eryth-, thre- etc) specify the configurations of the stereocentres relative to one another • D and L assignments do not necessarily reflect direction of rotation of polarised light  as opposed to d (+) and l (-) CHEM1222 – Chemistry for Pharmacy and Dentistry

Forming the hemiacetal ring structure

• Carbohydrates contain carbonyl (C=O) and alcohol (-OH) groups in the one molecule • Aldehydes and ketones react with alcohols to form hemiacetals  (Remember aldehyde and ketone lectures)

Glucopyranose ring

 Hemiacetals are more stable when a 5- or 6-membered ring is formed β = C-1 OH on same side of ring as CH2OH substituent (C5) α = C-1 OH on opposite side of ring to CH2OH substituent (C5)

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Cyclic monosaccharides

Cyclic monosaccharides http://www.chemeddl.org/resources/models360/model s.php?pubchem=107526 http://www.chemeddl.org/resources/models36 0/models.php?pubchem=79025

Haworth projections

• 6-membered hemiacetal rings are known as a pyranoses • 5-membered hemiacetal rings are known as a furanoses

• New stereocentre created upon cyclisation known as anomeric carbon ( anomers) • β form has the anomeric OH on the same side of the ring as the terminal CH2OH • • α form has the anomeric OH on the opposite side to the terminal CH2OH CHEM1222 – Chemistry for Pharmacy and Dentistry

• Chair conformations better represent the structures of pyranoses CHEM1222 – Chemistry for Pharmacy and Dentistry

Important monosaccharides The most abundant hexoses in the biological world are:  D-glucose (dextrose; blood)  D-galactose (dairy products)  D-fructose (honey, fruit) Amino sugars are common in nature:  D-glucosamine derivatives are major components of cartilage and chitin

D-galactose

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Formation of N-glycosides

Formation of glycosides (acetals)

Hemiacetals can also react with amines to form N-glycosides

Hemiacetals react with excess alcohol in the presence of an acid catalyst to form acetals • (Remember aldehyde and ketone lectures)

• N-glycosides formed from D-ribose and the aromatic bases above are especially important biologically  structural units of nucleic acids (nucleosides)

• The cyclic acetal derived from a monosaccharide is called a glycoside

cytidine CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Oxidation of monosaccharides

Reduction of monosaccharides

positive Tollens’ test

Carbonyl groups (C=O) of monosaccharides can be reduced to alcohols (-OH) by reductants such as NaBH4 • (remember previous lectures) H

• Reduction of monosaccharides  alditols • Alditols have no carbonyl group so cannot form cyclic hemiacetals • Alditols taste sweet  artificial sweeteners CHEM1222 – Chemistry for Pharmacy and Dentistry

HO H

CH2OH OH H OH CH2OH xylitol

• Aldehyde groups in aldoses are readily oxidised to give carboxylic acids (CO2H) • Oxidation of monosaccharides  aldonic acids • Carbohydrates which can be oxidised in this way are known as reducing sugars • This forms the basis of the Tollens’ test (Ch. 20; 863)

CHEM1222 – Chemistry for Pharmacy and Dentistry

Disaccharides

Lactose (dairy)

• Disaccharides consist of two monosaccharide units linked by a glycosidic bond between the anomeric carbon of one and an -OH group of the other • Sucrose (table sugar) Maltose (malt from barley  beer, whiskey etc)

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

2015 Exam Question

Polysaccharides Polysaccharides are polymers of monosaccharide units joined by glycosidic bonds Major classes: • • • •

Starch Glycogen polymers of D-glucose Cellulose Chitin - polymer of N-acetylglucosamine

Roles: • Energy storage • Structural CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Cellulose

Starch and glycogen Branching point

• Polymers of D-glucose • Branched structures • Starch  Carbohydrate storage in plants (seeds & tubers)  24-30 glucose units per branch  Joined by α-1,4- and α-1,6-glycosidic bonds

• Glycogen  Carbohydrate reserve in animals (liver / muscles)  12-14 glucose units per branch  Joined by α-1,4- and α-1,6-glycosidic bonds CHEM1222 – Chemistry for Pharmacy and Dentistry

• Most abundant plant skeletal polysaccharide • A linear polymer of D-glucose joined by β-1,4-glycosidic bonds • On average, ~2800 glucose units per molecule • Forms rod-like insoluble fibres due to strong hydrogen bonding between -OH groups from parallel chains • Humans lack β -glycosidases, so can’t digest cellulose CHEM1222 – Chemistry for Pharmacy and Dentistry

Chitin

• ß-1-4 linked units of N-acetylglucosamine

CHEM1222 • Chitin and chitosan (a derivative) are industrially important materials  Binders, resins, membranes, food additives, medicine, water purification etc CHEM1222 – Chemistry for Pharmacy and Dentistry

Chemistry for Pharmacy and Dentistry CHEM1222 – Chemistry for Pharmacy and Dentistry

Amino acids & proteins – lecture overview CHEM1222 Chemistry for Pharmacy and Dentistry

• What are amino acids? • Where do we find them and what do they do? • Different classes • Structures

• Reactivity Lecture 12 Molecules of life: Amino acids & proteins

• Formation of glycosides • Reduction • Oxidation Blackman etal. 4th Edition Chapter 24

CHEM1222 – Chemistry for Pharmacy and Dentistry

Amino acids and proteins

Blackman Chapter 24

CHEM1222 – Chemistry for Pharmacy and Dentistry

Amino acids – general structure β,ɣ …

• Amino acids are the building blocks of proteins • Contain basic (amine) and acidic (carboxylic acid) functional groups • important in contributing to protein properties

α

Protein roles • Structure (keratin, collagen) • Catalysis (enzymes) • Movement (muscle actin and myosin) • Transport (haemoglobin, albumin) • Protection (immune system, antibodies)

CHEM1222 – Chemistry for Pharmacy and Dentistry

α-amino acids • Acidic (-CO2H) and basic (-NH2) groups form an internal salt  “zwitterion” vs • No net charge CHEM1222 – Chemistry for Pharmacy and Dentistry

Amino acid stereochemistry • All natural amino acids are chiral • have at least 1 stereocentre (α-C) • (except glycine; R = H)

Protein-derived amino acids There are 20 proteinogenic amino acids • 19 contain a stereocentre at the α-carbon • All are L-amino acids • Glycine is not chiral (R = H)

• 19 contain a primary α-amine group • Except proline (secondary amine)

• To understand amino acid behaviour we need to consider: enantiomers

• The majority of biological α-amino acids are L-series • L-series are mostly S-stereoisomers (except cysteine) CHEM1222 – Chemistry for Pharmacy and Dentistry

1. 2. 3. 4.

Polarity and likely non-covalent interactions Acid-base behaviour Chemical reactivity Size, shape and rigidity

CHEM1222 – Chemistry for Pharmacy and Dentistry

Protein-derived amino acids

Non-polar side chains

Four categories of amino acid: 1. 2. 3. 4.

Non-polar side chains Polar, un-ionised side chains Acidic side chains Basic side chains

(hydrophobic) (hydrophilic) (hydrophilic) (hydrophilic)

2° α-amine

Naming: • common names (e.g. Alanine, Glycine) • 3 letter abbreviations (e.g. Ala, Gly) • 1st letter is always a capital • 1 letter abbreviations (e.g. A, G)

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Polar un-ionised side chains

Acidic and basic side chains Basic

Acidic

amide

1° alcohol

amide

2° alcohol

• Here, the side chains readily form hydrogen bonds

thiol

• N.B. Structures shown are dominant form at pH = 7.4 CHEM1222 – Chemistry for Pharmacy and Dentistry

Which of the following pairs of amino acids might contribute to protein structure by forming electrostatic interactions at physiological pH?

CHEM1222 – Chemistry for Pharmacy and Dentistry

Acid-base properties of amino acids Amino acids contain basic (amine) and acidic (carboxylic acid) functional groups • Some also contain ionisable side chains (basic or acidic )

A. Glycine and Leucine B. Glutamatic acid and Lysine C. Phenylalanine and Tyrosine D. Lysine and Arginine

• α-Carboxyl is a stronger acid than acetic acid (pKa = 4.74) • Due to inductive effect of α-NH3+ group • electron withdrawing

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Peptides and proteins

Acid-base properties of amino acids

1902: Emil Fischer proposed that proteins are long chains of amino acids joined by amide bonds between the α-carboxyl group of one amino acid and the α-amino group of the next.

Side chain carboxyl groups

 the peptide bond pKa = 3.86

pKa = 4.07

α-ammonium (-NH3+) groups

• Peptide = short polymer of amino acids • dipeptides, tripeptides, tetrapeptides etc • 10-20 amino acids  oligopeptide • >20 amino acids  polypeptide

• Proteins • Slightly stronger acid than primary aliphatic amine • Slightly weaker base than primary aliphatic amine CHEM1222 – Chemistry for Pharmacy and Dentistry

The peptide bond

• Biological macromolecules • Consist of one or more polypeptide chain • Molar mass >5000

haemoglobin

CHEM1222 – Chemistry for Pharmacy and Dentistry

• The peptide bond is a resonance hybrid of 2 contributing structures

• Accordingly, the atoms of the amide group and the 2 adjacent α-carbon atoms are co-planar

Peptide bond = amide bond between 2 amino acids CHEM1222 – Chemistry for Pharmacy and Dentistry

• The trans configuration is more favourable (sterically) CHEM1222 – Chemistry for Pharmacy and Dentistry

What are the amino acids in the peptide sequence of thymopentin?

Structural hierarchy Primary (1°)  Secondary (2°)  Tertiary (3°)  Quaternary (4°)

Asparagine should be Aspartic Acid

1°

2° 3°

Identify the peptide bonds (amides, boxed) then identify the side chains RKDVY L-arginyl-L-lysyl-L-α-aspartyl-L-valyl-L-tyrosine CHEM1222 – Chemistry for Pharmacy and Dentistry

4°

CHEM1222 – Chemistry for Pharmacy and Dentistry

21 Naturally Occurring Amino Acids

Primary (1°) structure The sequence of amino acids in the polypeptide chain

• Written from left to right • Amino acid with free –NH3+ group is first (N-terminal) • Amino acid with free –COO− group is last (C-terminal)

CHEM1222 – Chemistry for Pharmacy and Dentistry

https://en.wikipedia.org/wiki/File:Amino_Acids.svg

• Convention

All the alphabet but no: ‘B’, ‘J’, ‘O’, ‘X’ & ‘Z’!

CHEM1222 – Chemistry for Pharmacy and Dentistry

Selenocysteine is 21st!

Secondary (2°) structure Ordered arrangement of amino acid residues in localised regions (based on hydrogen bonding) • 2 common motifs; α-helix, β-sheet

α-helix

Secondary (2°) structure Anti-parallel β-pleated sheet = R group H-bonds

Poly(L-alanine)

= CH3 Right-handed helix H-bond 3.6 amino acids per turn Peptide bonds are trans & planar N-H points down; C=O points up R-groups point out from helix C=O hydrogen bonds to N-H within chain • 4 amino acids away • e.g. keratin in hair & wool, myosin

• • • • • •

CHEM1222 – Chemistry for Pharmacy and Dentistry

Tertiary (3°) structure

β-pleated sheet • 2 main types; parallel and anti-parallel • Refers to direction of adjacent polypeptide chains • C=O and N-H groups lie in the plane of the sheet • C=O groups of one chain hydrogen bonds to N-H groups of a neighboring chain • R groups in a given chain alternate between above and below the plane of the sheet CHEM1222 – Chemistry for Pharmacy and Dentistry

Tertiary (3°) structure

Overall folding pattern and arrangement in space (3D) of atoms in a single polypeptide chain Important interactions • Disulfide bonds (-S-S-) • Hydrophobic interactions • Hydrogen bonding • Salt linkages

Haem • Ribbon model of myoglobin • Stores O2 in muscle • 8 α-helix domains • Hydrophobic interactions direc • External hydrophilic R-groups  Hydrogen bonding with H2 • Several salt linkages

CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Quaternary (4°) structure • Most large proteins (Mw >50 000) consist of 2 or more polypeptide chains • Non-covalently linked • Same interactions that influence 3° structures

• e.g. Haemoglobin • O2 transport • 4 polypeptide chains • 2 x α-chains • 141 amino acids • 2 x β-chains • 146 amino acids CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 Chemistry for Pharmacy and Dentistry

Lecture 13 Molecules of life: Nucleic acids CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 Chemistry for Pharmacy and Dentistry CHEM1222 – Chemistry for Pharmacy and Dentistry

• Nucleoside is composed of an pentose monosaccharide (ribose or 2deoxy-D-ribose) bonded through C1’ (anomeric carbon) of the sugar to a heterocyclic base (purine or pyrimidine) by a 𝛽-N-glycosidic bond.

Uridine: a nucleoside derived from ribose and uracil CHEM1222 – Chemistry for Pharmacy and Dentistry

Blackman Chapter 25

Heterocyclic aromatic amine bases in DNA + RNA

• Nucleotide is a nucleoside in which a single phosphate group has been esterified with a hydroxyl group (commonly 3’ or 5’) on the monosaccharide ring.

adenosine 5’-monophosphate

2’-deoxyadenosine 5’-monophosphate

2’-deoxyadenosine 3’-monophosphate

The phosphate group is deprotonated (fully ionized) at pH 7.4 CHEM1222 – Chemistry for Pharmacy and Dentistry

CHEM1222 – Chemistry for Pharmacy and Dentistry

Primary Structure of DNA

Phosphorylation • Phosphorylation of a nucleoside monophosphate results in a nucleoside diphosphate and a nucleoside triphosphate. • This is achieved through a series of biochemical pathways in cells.

Adenosine 5’-triphosphate ATP 𝛾 phosphate

𝛽 phosphate

CHEM1222 – Chemistry for Pharmacy and Dentistry

𝛼 phosphate

3’ hydroxyl of one deoxyribose unit is joined by a phosphodiester bond to the 5’ hydroxyl of the next deoxyribose unit

Deoxyribose nucleic acid (DNA) is a polymer sequence of heterocyclic bases connected through the 2’-deoxyribosephosphodiester backbone. Bases are read from the 5’ end to the 3’ end. CHEM1222 – Chemistry for Pharmacy and Dentistry

Oligonucleotides • Research into the function and properties of DNA considers patterns of sequences of bases and so shorter sequences of heterocyclic bases, often referred to as oligonucleotides, are commonly synthesized in a laboratory for this purpose.

NH2

NH2 N O

OH 5'

CH2

N

O H

H

H

O

1' H

H 5' P O CH2

O-

O

This is the structural formula for a section of DNA that contains the base sequence CTG and is phosphorylated at the 3’ end only.

O