2.5: Basic Biochemistry- Monomers, Polymers, Macromolecular Synthesis, Degradation

Like evolution, the origin of life involved a prebiotic chemical selection—a kind of "natural selection” of environmental chemicals that favored increasing biochemical possibilities and diversity.

In simple terms, atoms that could interact with a maximal number of other atoms to form the largest number of stable molecules would have been most likely to accumulate in the environment. The tetravalent C atom met these criteria for chemical selection, proving ideal for building an organic chemistry set.

At the same time, water turned out to be the perfect place to launch prebiotic chemical selection experiments. Water persists as life’s universal solvent, which explains why evidence of water in places beyond our Earth (e.g.,other planets in our solar system, the moons of other planets, and other planets in other solar systems) gets us all excited!

2.5.1. Isomerism in Organic Molecules and the Diversity of Shape

The carbon skeleton is a perfect platform for organic molecule diversity. The different possible arrangements of atoms and functional chemical groups around C atoms result in isomerism. Isomers of an organic molecule have the same chemical formula but different shapes, and thus, potentially different chemical properties and biochemical functions. The larger the C-skeleton of an organic molecule, the greater the diversity of molecular shapes available for chemical selection. Look at the examples of structural isomers and geometric isomers in Figure 2.10.

Figure 2.10: Structural and geometric isomers of hydrocarbons create molecules with the same chemical formula but different shapes.

It is easy to see that the structural isomers of \(\rm C_4H_{10}\) (Figure 2.10, top panel, left and right) have different shapes. You cannot convert one structural isomer to the other without breaking covalent bonds. In the geometric isomers of \(\rm C_4H_8\) in the lower panel, the H atoms on the double-bonded C atoms can be on the same (cis) or opposite (trans) side of the planar double bond. Geometric isomers, too, cannot be interconverted without breaking chemical bonds. Optical isomers are a third kind of isomer. They exist around optically active (asymmetric or chiral) carbons. A chiral C is one that is covalently linked to four different atoms and/or molecular groups.

The principle of chirality is illustrated in Figure 2.11.

Figure 2.11: The two different generic molecules (enantiomers) are mirror images of one another. They form from alternate arrangements of the same molecular groups around a chiral carbon.

Optical isomers (also called enantiomers) also differ in shape, and just like structural and geometric isomers, they can’t be converted from one to the other without breaking and remaking covalent bonds. Enantiomers are defined as optically active because they bend or rotate light in opposite directions in a polarimeter: light passing through a solution of one optical isomer is rotated in one direction, while light passing through the other isomer is rotated in the opposite direction. These directions are referred to as l for levo (meaning left) and d for dextro (meaning right). If a molecule has more than one chiral C (e.g., glucose has four chiral carbons), its behavior in a polarimeter will be based on the sum of the optical activities of all the chiral carbons. The common isomer of glucose in our diet is (d) glucose.

Glucose enantiomers are also referred to as D and L, a convention based on the configuration of the four different atoms or groups around the last optically active carbon in a molecule. This is C5 in glucose, as shown in Figure 2.12.

Figure 2.12: Two straight-chain forms of glucose- (d) glucose and (l) glucose-are enantiomers (optical isomers), differing in the arrangement of the H atom and the OH group around C5.

For glucose, d and l in fact correspond to D and L, respectively. As we will see for some molecules, the uppercase designation of a chiral molecule does not always indicate how it bends light in a polarimeter, while the lowercase d and l always do! The chiral carbons in glucose are shown in red above.

Remember that the shape and chemical properties of a molecule dictate its function. Isomerism in organic (carbon-based) molecules would have increased the diversity of molecular shapes available for chemical selection. Early selection of isomers (specific optical isomers in particular) during chemical evolution contributed greatly to the chemical functions and reactions we recognize in cells now, even before there was life on Earth. All life uses the same isomers of glucose in energy reactions and of amino acids in protein-building, a fact that confirms the prebiotic selection of those isomers!

2.5.2. Monomers to Polymers and Back: Dehydration Synthesis and Hydrolysis

All living things build and break down polymers (macromolecules) by dehydration synthesis (condensation reactions) and hydrolysis, respectively. Dehydration synthesis and hydrolysis reactions are essentially the reverse of each other (Figure 2.13).

Figure 2.13: A generic monomer is linked to a growing polymer by water removal (dehydration synthesis). Water addition across the linkage between monomers (hydrolysis) breaks the polymer back down to monomers.

Condensation reactions build macromolecules by removing a water molecule from interacting monomers. The “bond” that forms in a condensation reaction is not a single bond; rather, it is a linkage involving several bonds! Polymer synthesis happens when an OH from one monomer and an H group from another are removed and combine to form a water molecule.

126 Organic Molecules, Monomers, & Polymers

Cells perform repeated dehydration synthesis reactions to build diverse polymers, including polysaccharides and polynucleotides (the RNA and DNA nucleic acids). Repeated condensation reactions between two amino acids (Figure 2.14, below) form the peptide linkages that build polypeptides during translation.

Figure 2.14: Dehydration synthesis forms peptide linkage (circled) between amino acid monomers. Hydrolysis, the reverse reaction is also shown. Hydrolysis, the reverse reaction is also shown.

Next let’s consider the polymerization of glucose. Natural selection settled on using the (d)glucose optical isomer for energy metabolism–all living things do it! And none of them, with one known exception (a plant bacterial pathogen)either contain or use the (l)glucose isomer. In solution, straight-chain (d)glucose becomes cyclic as shown in Figure 2.15.

Figure 2.15: When straight-chain glucose forms a cyclic molecule in solution in water, C1 becomes optically active (chiral), creating a racemic mixture of \(\alpha\)(d)glucose and \(\beta\)(d)glucose enantiomer

The –OH ions (hydroxyl groups) on the C1 of \(\alpha\)(d)glucose are below the glucose rings. The condensation reaction removes a water molecule, linking the sugars by an \(\textbf{\alpha}\)1,4 glycoside linkage in the dimer, connecting them by their C1 and C4 carbons. Other linkages are possible. For example, diverse \(\alpha\)-glycoside linkages characterize branched storage polysaccharides—like glycogen in animals and starches in plants. On the other hand, when \(\textbf{\beta}\)(d)glucose enantiomers polymerize, they form rigid structural polysaccharides, such as those of cellulose in plant cell walls. A modified \(\beta\)-glucose called N-acetyl glucosamine (not shown) polymerizes to form chitin, the principal component of fungal cell walls and of the tough exoskeleton of arthropods (e.g., insects and crustaceans). Later, when we look at how translation links amino acids to make a polypeptide, we’ll consider why only L amino acids are used! We also look at replication and transcription, condensation reactions that form the phosphate (phosphodi-)ester linkages in DNA and RNA synthesis from nucleotide monomers.

Summarizing the role of condensation reactions in the formation of biological polymers:

• Linkages in these biopolymers are broken and formed daily in our lives! After a protein- and carb-containing meal, digestion, the hydrolysis of glycoside and peptide linkages, begins in your mouth and continues in your stomach and small intestines. Then our cells use condensation reactions to complete the job of turning carrot- and cow-derived monomers into you or me!
• Prebiotic chemical evolution has selected only one of the optical isomers (enantiomers) of glucose, amino acid and other monomers with which to build polymers. This is so even though some of the different isomers are available and even used for different purposes. The flexible a(d)glucose polymer was selected to be the storage polysaccharides that we use for energy, a selection probably made by cells themselves. Storage polysaccharides include the plant starches and animal glycogen. Likewise, the rigid inflexibility of b(d)glucose polymers would have been selected to reinforce cell structure and stability. Since all organisms store carbohydrate energy in a(d)glucose polymers and since b(d)glucose polymers are almost universally used to strengthen cell structure, these selections must have occurred early in the history of life.

127-2 Carbohydrates: Sugar and Polysaccharides

128-2 Lipids, Triglycerides, and Phospholipids

129-2 Proteins: Amino Acids and Polypeptides

130-2 130-2 Nucleic Acids: Nucleotides, DNA, and RNA

2.5.3. A Tale of Chirality Gone Awry

To conclude this chapter and to emphasize the significance of chirality to life, here is what can happen when the wrong isomer ends up in the wrong place at the wrong time…

Consider the story of thalidomide, a tragic example of what happens when we are unaware of enantiomeric possibilities. Introduced in 1957, thalidomide was sold as an over-the-counter anti-nausea drug for patients undergoing cancer therapies and as a very effective morning-sickness remedy for pregnant women. However, by the early 1960s, the births of about ten thousand infants with severely deformed limbs were connected to the drug. These deformities characterized roughly half of these infants that survived. Once the connection was made, the response was, of course, to pull thalidomide off the market.

Thalidomide is a teratogen. Teratogens are substances or conditions (drugs, chemicals, radiation, illness during pregnancy, etc.) that cause deformities during embryogenesis and fetal development. The chemical basis of Thalidomide’s effects are based on its enantiomeric (chiral) structure in which an amine-containing ring can exist in front of, or behind the rest of the molecule. The structure of thalidomide is shown in Figure 2.17.

Figure 2.17: Two enantiomers (optical isomers) of thalidomide (R and S) form in water.

The two enantiomers are referred to as “S” and “R.” Of these, the S isomer is the teratogen. While synthesis of pure R is possible, when used in treatment, R and S easily interconvert, creating a racemic mixture (recall that \(\alpha\)- and \(\beta\)-(d)glucose) are such a solution. In the mother, S isomers are transferred to the embryo or fetus, with terrible consequences.

Remarkably, there were relatively few cases of thalidomide-induced birth deformities in the United States, largely because of the efforts of Frances Oldham Kelsey, the person in charge of the FDA’s review of the drug. The German pharmaceutical company Chemie Grünenthal (developer of Thalidomide) and an American pharmaceutical company had applied for FDA approval for US distribution of the drug. Dr. Oldham Kelsey refused approval on multiple occasions, arguing that the safety of thalidomide had not been demonstrated. This was even before it was shown to cause birth deformities! In 1962 President John F.Kennedy presented her with the President’s Award for Distinguished Federal Civilian Service for not allowing thalidomide to be approved for sale in the United States without sufficient safety testing—potentially saving thousands of lives.

Of course, we already knew that cells synthesized polymers from specific optical isomers of their precursor monomers. So the sad thalidomide story resulted from the untested effects of an unexpected optical isomer. Many countries quickly tightened their preapproval drug-testing regulations because of this tragedy.

In a more hopeful twist of the tale, thalidomide has turned out to be effective in treating cancer, leprosy, rheumatoid arthritis, and other autoimmune diseases. Such therapeutic benefits may be due to its anti-inflammatory effects. The effects of thalidomide on tumor growth seem to be due to its inhibition of angiogenesis (development of blood vessels) in the tumors. Ironically, blockage of angiogenesis may also have contributed to the failure of proper limb growth during pregnancy.

To conclude, when all is normal, the shapes of molecules have been uniquely selected for the specificity of reactions essential to life.

131-2 Shape and the Specificity of Molecular interactions