LEHNINGER PRINCIPLES OF BIOCHEMISTRY - VOL. 1. THE FOUNDATIONS OF BIOCHEMISTRY: STRUCTURE AND CATALYSIS - 2011

1. THE FOUNDATIONS OF BIOCHEMISTRY

1.4. Genetic Foundations

Perhaps the most remarkable property of living Cells and organisms is their capacity to reproduce their own kind with near-perfect fidelity through countless generations. This continuity of inherited traits over millions of years implies a constancy in The Structure of the molecules that carry Genetic information. Few vestiges of human civilization, even those etched in metal or carved in stone (Fig. 1–29), have survived for more than a few thousand years. Yet there is evidence that the genetic instructions embodied in living organisms have remained virtually unchanged over incomparably longer periods. Many Bacteria share the same shape, size, and internal structure, and contain the same kinds of simple molecules and Enzymes, as bacteria that lived some four billion years ago. This uniformity of structure and composition is the result of the continuity of genetic material.

Class="center">Figure 1–29 Two ancient manuscripts. (a) The Prism of Sennacherib, dating from the 7th century BC. This prism recounts historical events during the reign of the Assyrian king Sennacherib in the Assyrian language. It contains about 20,000 characters, weighs approximately 50 kg, and has survived almost intact for 2,700 years. (b) A single DNA molecule from an E. coli bacterium, spilled from a lysed Cell. The DNA molecule is hundreds of times longer than The Cell itself and contains all the information needed to specify the cell's Structure and function. The bacterial DNA contains about 4.6 million characters (NUCLEOTIDES), weighs less than 10^-10 g, and has remained virtually unchanged for millions of years. (The yellow patches and black dots in this stained electron micrograph are artifacts of Sample preparation.)

Among the most momentous discoveries in 20th-century biology was the chemical nature and three-dimensional STRUCTURE OF THE genetic substance: deoxyribonucleic acid, or DNA. The sequence of monomeric units (nucleotides, or more specifically, deoxyribonucleotides) in this linear polymer encodes the instructions for synthesizing all other cellular components and serves as a template for generating identical DNA molecules passed on to progeny during Cell Division. The continuity of a biological species requires that its genetic information be stored in a stable form, expressed accurately, and replicated with minimal errors. The efficient storage, expression, and Replication of genetic information define an individual species, distinguish it from others, and ensure its survival across subsequent generations.

Genetic heredity is anchored in DNA molecules

DNA is a long, thin organic polymer molecule. It is one of the rare molecules that has atomic dimensions in one dimension (width) and human-scale dimensions in another (a DNA molecule can be several centimeters long). Human sperm cells and eggs, carrying hereditary information accumulated over billions of years of evolution, transmit it in the form of DNA molecules, in which the genetic information is encoded in the linear sequence of covalently linked nucleotide units.

Normally, when we describe The properties of chemical substances, we refer to the averaged characteristics of a vast number of identical molecules. It is difficult to predict The behavior of a single molecule out of a collection, say, containing 1 pmol of a substance (≈ 6 · 10¹¹ molecules), whereas averaged properties are entirely predictable because they deal with large numbers of molecules. Cellular DNA is an exception. The entire genetic material of E. coli is contained within a single DNA molecule comprising 4.64 million nucleotides. If an E. coli cell is to produce identical progeny through cell division, this single DNA molecule must replicate itself down to the minutest detail; there is no room for averaging here! The same holds true for all cell types. A human sperm cell brings into the egg it fertilizes just a single DNA molecule for each of the 23 distinct Chromosomes, which combine with only a single DNA molecule in each corresponding chromosome of the egg. The outcome of this union is entirely predictable—an embryo with all its ≈25,000 genes composed of 3 billion nucleotides. A staggering chemical phenomenon!

■ Box 1–1. The Accuracy of METABOLISM/36.html">DNA replication

How many times has the DNA of an E. coli bacterium replicated to date, given that the very first cell of this species appeared 3.5 billion years ago? To keep things simple, assume that throughout this time, E. coli cell division occurred once every 12 hours (this is far too slow for modern bacteria, but perhaps too fast for their ancient precursors).

Solution.

(1 division/12 h) · (24 h/day) · (365 days/year) · (3.5 · 10⁹ years) = 2.6 · 10¹² generations.

A single page of this book contains nearly 5,000 characters, meaning the entire book has about 5 million characters. The E. coli chromosome also contains about 5 million characters (Base Pairs). Suppose you copy this book out by hand, then a classmate copies your copy, then a third classmate copies that copy, and so on. How drastically would each successive copy differ from the original? Now imagine the textbook that would result from copying a book 10¹² times!

Introduction/20.html">DNA Structure allows for Replication and Repair with near-absolute fidelity

The ability of living cells to preserve their genetic material and duplicate it for transmission to the next generation stems from the complementarity of the two strands that make up the DNA molecule (Fig. 1–30). The fundamental unit of DNA is a linear polymer built from four different monomeric units, deoxyribonucleotides, arranged in a strictly defined linear sequence. It is precisely this linear sequence that encodes genetic information. Two such polymer strands wind around each other to form a DNA double helix, in which each deoxyribonucleotide on one strand forms a specific pair with a complementary deoxyribonucleotide on the opposite strand. Before a cell divides, the two DNA strands part, and each serves as a template for the synthesis of a new complementary strand, producing two identical double-stranded molecules—one for each of the two daughter cells. If one strand is damaged, the preservation of genetic information is ensured by the presence of the second strand, which serves as a template for repairing the damage.

Figure 1–30 Complementarity of the two DNA strands. DNA is a linear polymer of covalently linked deoxyribonucleotides of four types: deoxyadenylate (A), deoxyguanylate (G), deoxycytidylate (C), and deoxythymidylate (T). Each nucleotide has a specific three-dimensional structure and can specifically (noncovalently) bind to one nucleotide in the complementary chain: A always pairs with T, and G always pairs with C. Thus, in a double-stranded DNA molecule, the complete nucleotide sequence of one strand is complementary to the sequence of the other strand. The two chains (or strands) are held together by Hydrogen Bonds (indicated by vertical light-blue bars) formed between all nucleotide pairs. In addition, the two DNA strands wind around each other to form a double helix. During DNA replication (duplication), the two strands (blue) separate, and two new strands (red) are synthesized, each complementary to one of the parental strands. This yields two double-stranded DNA molecules identical to the original molecule.

The linear sequence of DNA encodes Proteins with three-dimensional structure

Information in DNA is encoded as a linear (one-dimensional) sequence of deoxyribonucleotide units, yet the expression of this information results in three-dimensional cellular structures. This transition from one dimension to three unfolds in two stages. The linear sequence of deoxyribonucleotides in DNA specifies (via an intermediate RNA stage) a protein with a corresponding linear sequence of Amino Acids (Fig. 1–31). The protein adopts a specific three-dimensional shape determined by its Amino Acid Sequence and stabilized primarily by noncovalent interactions. Although the final shape of the folded protein is dictated by its amino acid sequence, the assembly (folding) process often requires the assistance of "molecular chaperones" (see Fig. 4–29). The precise three-dimensional structure of a protein, i.e., its native conformation, is a prerequisite for its proper function.

Figure 1–31 From DNA to RNA, to protein, and thence to enzyme (using hexokinase as an example). The linear sequence of deoxyribonucleotides in DNA encoding the enzyme hexokinase is first transcribed into a complementary sequence of ribonucleotides (RNA). Next, the RNA sequence (Messenger RNA) is translated into a linear protein chain, which folds into a strictly defined Spatial Structure, likely with the assistance of molecular chaperones. Having attained its native conformation, the hexokinase molecule exhibits catalytic activity: it catalyzes the phosphorylation of glucose, using ATP as a phosphoryl group donor.

Proteins in their native conformation can form noncovalent complexes with other macromolecules (other proteins, Nucleic Acids, or Lipids), giving rise to supramolecular structures such as chromosomes, Ribosomes, and membranes. The molecules making up these complexes possess specific high-affinity binding sites for other molecules within the assembly, allowing them to spontaneously assemble into functional machinery inside the cell.

Although the protein sequence itself carries the necessary information for correct folding and adoption of the native conformation, the success of this process nonetheless depends on intracellular conditions—pH, Ionic strength, metal ion concentration, and so forth. Therefore, the DNA sequence alone is not sufficient for the generation of cellular structures.

Summary of Section 1.4 Genetic foundations of Biochemistry

■ Genetic information is encoded in the linear sequence of four types of deoxynucleotides within DNA.

■ The DNA double helix serves as a template for its own replication and repair.

■ The linear sequence of amino acids in a protein, encoded by the protein's Gene, determines the protein's unique three-dimensional structure, which is also influenced by intracellular conditions.

■ Certain macromolecules with a high affinity for other macromolecules can spontaneously self-assemble into supramolecular complexes.