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Chapter 1: Nucleic Acid Structure and OrganizationCentral Dogma of Molecular BiologyNucleotide Structure and NomenclatureNucleic Acids Organization of DNAReview QuestionsReview Questions

USMLE® STEP 1:

BIOCHEMISTRY AND MEDICAL

GENETICS

Lecture Notes

2019

Chapter 1: Nucleic Acid Structure and Organization

Central Dogma of Molecular BiologyNucleotide Structure and NomenclatureNucleic Acids

Organization of DNAReview QuestionsReview Questions: Answers and ExplanationsChapter 2: DNA Replication and Repair

DNA ReplicationComparison of DNA and RNA SynthesisSteps of DNA Replication

DNA RepairReview QuestionsReview Questions: Answers and ExplanationsChapter 3: Transcription and RNA Processing

TranscriptionTypes of RNARNA PolymerasesTranscription: Important Concepts and TerminologyProduction of Prokaryotic Messenger RNA

Production of Eukaryotic Messenger RNAAlternative Splicing of Eukaryotic Primary Pre-mRNATranscripts

Ribosomal RNA (rRNA) is Used to Construct RibosomesTransfer RNA (tRNA) Carries Activated Amino Acids forTranslation

Review Questions

Review Questions : Answers and Explanations

Chapter 4: The Genetic Code, Mutations, and Translation

Inhibitors of Protein Synthesis

Protein Folding and Subunit Assembly

Translation Occurs on Free Ribosomes and on the RoughEndoplasmic Reticulum

Co- and Posttranslational Covalent Modifications

Posttranslational Modifications of Collagen

Review Questions

Review Questions : Answers and Explanations

Chapter 5: Regulation of Eukaryotic Gene Expression

Genetic Regulation

Regulation of Eukaryotic Gene Expression

Review Questions

Review Questions : Answers and Explanations

Chapter 6: Genetic Strategies in Therapeutics

Recombinant DNA Technology

Cloning Restriction Fragments of DNA: the Human GenomeProject

Cloning Genes as cDNA Produced by Reverse Transcription

of Cellular mRNA

Medical Applications of Recombinant DNA

Review Questions

Review Questions : Answers and Explanations

Chapter 7: Techniques of Genetic Analysis

Blotting Techniques

Polymerase Chain Reaction (PCR)

Review Questions

Review Questions : Answers and Explanations

Chapter 8: Amino Acids, Proteins, and Enzymes

Hormones and Signal Transduction

Mechanism of Water-soluble Hormones

G Proteins in Signal Transduction

Metabolic Sources of Energy

Metabolic Energy Storage

Regulation of Fuel Metabolism

Patterns of Fuel Metabolism in Tissues

Review Questions

Review Questions : Answers and ExplanationsChapter 12: Glycolysis and Pyruvate DehydrogenaseOverview

Chapter 13: Citric Acid Cycle and Oxidative PhosphorylationCitric Acid Cycle

Electron Transport Chain

Review Questions

Review Questions : Answers and Explanations

Chapter 14: Glycogen, Gluconeogenesis, and the Hexose

Review Questions : Answers and Explanations

Chapter 15: Lipid Synthesis and Storage

Fatty Acid Nomenclature

Lipid Digestion

Fatty Acid Biosynthesis

Triglyceride (Triacylglycerol) Synthesis

Lipoprotein Metabolism

Hyperlipidemias

Cholesterol Metabolism

Review Questions

Review Questions : Answers and Explanations

Chapter 16: Lipid Mobilization and Catabolism

Lipid Mobilization

Fatty Acid Oxidation

Ketone Body Metabolism

Sphingolipids

Review Questions

Review Questions : Answers and Explanations

Chapter 17: Amino Acid Metabolism

S-Adenosylmethionine, Folate, and Cobalamin

Specialized Products Derived From Amino Acids

Heme Synthesis

Iron Transport and Storage

Bilirubin Metabolism

Review Questions

Review Questions : Answers and Explanations

Chapter 18: Purine and Pyrimidine Metabolism

Review Questions : Answers and Explanations

Part II: Medical Genetics

Chapter 1: Single-Gene Disorders

Basic Definitions

Major Modes of Inheritance

Important Principles That Can Characterize Single-GeneDiseases

Review Questions

Review Questions : Answers and Explanations

Chapter 2: Population Genetics

Basic Definitions and Terminology

Numerical Chromosome Abnormalities

Structural Chromosome Abnormalities

Other Chromosome Abnormalities

Advances in Molecular Cytogenetics

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University of Minnesota Medical School, Duluth Campus

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PART I

BIOCHEMISTRY

NUCLEIC ACID STRUCTURE

AND ORGANIZATION

Figure I-1-1 Central Dogma of Molecular Biology

Genetic information is stored in the base sequence of DNA molecules

Ultimately, during the process of gene expression, this information is used tosynthesize all the proteins made by an organism

Classically, a gene is a unit of the DNA that encodes a particular protein or

RNA molecule Although this definition is now complicated by our increasedappreciation of the ways in which genes may be expressed, it is still useful as

a working definition

GENE EXPRESSION AND DNA

REPLICATION

Gene expression and DNA replication are compared below Transcription,the first stage in gene expression, involves transfer of information found in adouble-stranded DNA molecule to the base sequence of a single-strandedRNA molecule If the RNA molecule is a messenger RNA, then the processknown as translation converts the information in the RNA base sequence tothe amino acid sequence of a protein

When cells divide, each daughter cell must receive an accurate copy of thegenetic information DNA replication is the process in which each

chromosome is duplicated before cell division

Table I-1-1 Comparison of Gene Expression and DNA Replication

Produces all the proteins an organism requires Duplicates the chromosomes before cell

division Transcription of DNA: RNA copy of a small section of

a chromosome (average size of human gene, 104–105

nucleotide pairs)

DNA copy of entire chromosome (average size of human chromosome,

108 nucleotide pairs) Transcription occurs in the nucleus throughout

interphase

Occurs during S-phase

Translation of RNA (protein synthesis) occurs in the

cytoplasm throughout the cell cycle

Replication in nucleus

The concept of the cell cycle can be used to describe the timing of some ofthese events in a eukaryotic cell The M phase (mitosis) is the time in whichthe cell divides to form 2 daughter cells Interphase describes the time

between 2 cell divisions or mitoses Gene expression occurs throughout allstages of interphase Interphase is subdivided as follows:

Figure I-1-2 Eukaryotic Cell Cycle

G1 phase (gap 1) is a period of cellular growth preceding DNA synthesis.Cells that have stopped cycling, such as muscle and nerve cells, are said to

be in a special state called G0

S phase (DNA synthesis) is the period of time during which DNA

replication occurs At the end of S phase, each chromosome has doubledits DNA content and is composed of 2 identical sister chromatids linked atthe centromere

G2 phase (gap 2) is a period of cellular growth after DNA synthesis butpreceding mitosis Replicated DNA is checked for any errors before celldivision

Many chemotherapeutic agents function by targeting specific phases of the cell cycle This is

a frequently tested area on the exam

Some commonly tested agents with phase of cell cycle they target:

Control of the cell cycle is accomplished at checkpoints between the variousphases by strategic proteins such as cyclins and cyclin-dependent kinases.These checkpoints ensure that cells will not enter the next phase of the cycleuntil the molecular events in the previous cell cycle phase are concluded

Reverse transcription, which produces DNA copies of an RNA, is morecommonly associated with life cycles of retroviruses, which replicate andexpress their genome through a DNA intermediate (an integrated provirus).Reverse transcription also occurs to a limited extent in human cells, where itplays a role in amplifying certain highly repetitive sequences in the DNA(Chapter 7)

S-phase: methotrexate, 5-fluorouracil, hydroxyurea

G2 phase: bleomycin

M phase: paclitaxel, vincristine, vinblastine

Non cell-cycle specific: cyclophosphamide, cisplatin

NUCLEOTIDE STRUCTURE AND NOMENCLATURE

Nucleic acids (DNA and RNA) are assembled from nucleotides, which

consist of 3 components: a nitrogenous base, a 5-carbon sugar (pentose), andphosphate

FIVE-CARBON SUGARS

Nucleic acids (as well as nucleosides and nucleotides) are classified

according to the pentose they contain If the pentose is ribose, the nucleicacid is RNA (ribonucleic acid); if the pentose is deoxyribose, the nucleic acid

is DNA (deoxyribonucleic acid)

There are 2 types of nitrogen-containing bases commonly found in

nucleotides: purines and pyrimidines

Figure I-1-3 Bases Commonly Found in Nucleic Acids

Purines contain 2 rings in their structure The purines commonly found innucleic acids are adenine (A) and guanine (G); both are found in DNA andRNA Other purine metabolites, not usually found in nucleic acids, includexanthine, hypoxanthine, and uric acid

Pyrimidines have only 1 ring Cytosine (C) is present in both DNA andRNA Thymine (T) is usually found only in DNA, whereas uracil (U) isfound only in RNA

NUCLEOSIDES AND NUCLEOTIDES

Nucleosides are formed by covalently linking a base to the number 1 carbon

of a sugar The numbers identifying the carbons of the sugar are labeled with

“primes” in nucleosides and nucleotides to distinguish them from the carbons

of the purine or pyrimidine base

Figure I-1-4 Examples of Nucleosides

Nucleotides are formed when 1 or more phosphate groups is attached to the 5′carbon of a nucleoside Nucleoside di- and triphosphates are high-energycompounds because of the hydrolytic energy associated with the acid

anhydride bonds

Figure I-1-5 Examples of Nucleotides

Figure I-1-6 High-Energy Bonds in a Nucleoside Triphosphate

The nomenclature for the commonly found bases, nucleosides, and

nucleotides is shown below Note that the “deoxy” part of the names

deoxythymidine, dTMP, etc., is sometimes understood and not expresslystated because thymine is almost always found attached to deoxyribose

Table I-1-2 Nomenclature of Important Bases, Nucleosides, and Nucleotides

Names of nucleosides and nucleotides attached to deoxyribose are shown in parentheses.

Adenine Adenosine (Deoxyadenosine) AMP (dAMP) ADP (dADP) ATP (dATP) Guanine Guanosine (Deoxyguanosine) GMP (dGMP) GDP (dGDP) GTP (dGTP) Cytosine Cytidine (Deoxycytidine) CMP (dCMP) CDP (dCDP) CTP (dCTP) Uracil Uridine (Deoxyuridine) UMP (dUMP) UDP (dUDP) UTP (dUTP)

NUCLEIC ACIDS

The base sequence of a nucleic acid strand is written by convention, in the5′→3′ direction (left to right) According to this convention, the sequence of

the strand on the left in Figure I-1-7 must be written 5′-TCAG-3′ or TCAG:

In eukaryotes, DNA is generally double-stranded (dsDNA) and RNA is

generally single-stranded (ssRNA) Exceptions occur in certain viruses, some

of which have ssDNA genomes and some of which have dsRNA genomes

Nucleotides linked by 3′, 5′ phosphodiester bonds

Have distinct 3′ and 5′ ends, thus polarity

Sequence always specified as 5′→3′

If written backward, the ends must be labeled: 3′-GACT-5′

The positions of phosphates may be shown: pTpCpApG

In DNA, a “d” (deoxy) may be included: dTdCdAdG

Figure I-1-7 Hydrogen-Bonded Base Pairs in DNA

DNA STRUCTURE

Using Chargaff’s Rules

In dsDNA (or dsRNA) (ds = double-stranded)

Some of the features of double-stranded DNA include:

The 2 strands are antiparallel (opposite in direction)

The 2 strands are complementary A always pairs with T (2 hydrogenbonds), and G always pairs with C (3 hydrogen bonds) Thus, the basesequence on one strand defines the base sequence on the other strand.Because of the specific base pairing, the amount of A equals the amount of

T, and the amount of G equals the amount of C Thus, total purines equalstotal pyrimidines These properties are known as Chargaff’s rules

With minor modification (substitution of U for T) these rules also apply todsRNA.

Most DNA occurs in nature as a right-handed double-helical molecule known

as Watson-Crick DNA or B-DNA The hydrophilic sugar-phosphate

backbone of each strand is on the outside of the double helix The bonded base pairs are stacked in the center of the molecule There are about

hydrogen-10 base pairs per complete turn of the helix A rare left-handed double-helicalform of DNA that occurs in G-C–rich sequences is known as Z-DNA Thebiologic function of Z-DNA is unknown, but may be related to gene

regulation

Figure I-1-8 B-DNA Double Helix

DENATURATION AND RENATURATION OF

DNA

Figure I-1-9 Denaturation and Renaturation of DNA

Double-helical DNA can be denatured by conditions that disrupt hydrogenbonding and base stacking, resulting in the “melting” of the double helix intotwo single strands that separate from each other No covalent bonds are

broken in this process Heat, alkaline pH, and chemicals such as formamideand urea are commonly used to denature DNA

Denatured single-stranded DNA can be renatured (annealed) if the denaturingcondition is slowly removed For example, if a solution containing heat-denatured DNA is slowly cooled, the two complementary strands can becomebase-paired again (Figure I-1-9).

Such renaturation or annealing of complementary DNA strands is an

important step in probing a Southern blot and in performing the polymerasechain reaction (reviewed in Chapter 7) In these techniques, a well-

characterized probe DNA is added to a mixture of target DNA molecules.The mixed sample is denatured and then renatured When probe DNA binds

to target DNA sequences of sufficient complementarity, the process is calledhybridization

RECALL QUESTION

Answer: D

Methotrexate affects which portion of the cell cycle?

G1 phaseA)

G2 phaseB)

M phaseC)

S phaseD)

ORGANIZATION OF DNA

Large DNA molecules must be packaged in such a way that they can fitinside the cell and still be functional

Mitochondrial DNA and the DNA of most prokaryotes are closed circularstructures These molecules may exist as relaxed circles or as supercoiledstructures in which the helix is twisted around itself in 3-dimensional space.Supercoiling results from strain on the molecule caused by under- or

overwinding the double helix:

Negatively supercoiled DNA is formed if the DNA is wound more looselythan in Watson-Crick DNA This form is required for most biologic

reactions

Positively supercoiled DNA is formed if the DNA is wound more tightlythan in Watson-Crick DNA

Topoisomerases are enzymes that can change the amount of supercoiling

in DNA molecules They make transient breaks in DNA strands by

alternately breaking and resealing the sugar-phosphate backbone For

example, in Escherichia coli, DNA gyrase (DNA topoisomerase II) can

introduce negative supercoiling into DNA