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BC1_1
Introduction Lecture 1
Nucleic Acid Components
Nucleic Acid Components
Nucleic Acid Composition
Chromosome Composition I
Chromosome Composition II
BC1_2
DNA Replication I
DNA Replication II
Telomerases
BC1_3
DNA Repair I
DNA Repair II
DNA Repair Mechanisms Summary
BC1_4
Overview of Transcription
Types of RNA
RNA Polymerases
Transcription Terminology
Flow of Genetic Information
Transcription of Eukaryotic mRNA
Co- and Postranscriptional Processing
Alternative Splicing
Ribosomes
tRNA
Genetic Code
Mutations
BC1_5
Translation
Translation: Initiation Phase
Translation: Elongation Phase
Translation: Termination Phase
Antibiotics
BC1_6
Protein Structure
Chaperones, Ubiquitin and Proteasomes
Rough ER versus Free Ribosomes
Co- and Post-translational Modification of Proteins
Golgi Apparatus
BC1_7
Post-translational Modification of Collagen
Types of Collagen
Disorders of Collagen
BC1_8
Peroxisome
Smooth Endoplasmic Reticulum
Microtubules
Chédiak–Higashi Syndrome
Cilia
Cytoskeletal Structures
BC2_1
Introduction Lecture 1
Chromatin Remodeling
Enhancers
Transcription Factors
Stimulation of Transcription
Key Specific Transcription Factors
BC2_2
Recombinant DNA
Recombinant Genomic DNA
Recombinant cDNA
BC2_3
DNA Libraries
Applications of Gene Cloning
BC2_4
Blotting Techniques
Types of Blots
Polymerase Chain Reaction
Polymerase Chain Reaction Sequence
Enzyme-Linked Immunosorbent Assay (ELISA)
BC3_1
Introduction Lecture 1
Definitions I
Definitions II
Pedigree
BC3_2
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance
X-Linked Recessive Inheritance
Recurrence Risk in X-Linked Recessive Inheritance
X-Linked Dominant Inheritance
Recurrence Risk in X-Linked Dominant Inheritance
Mitochondrial Inheritance
Algorithm for Determining Mode of Inheritance in Pedigree
BC3_3
Factors Influencing Phenotypic Expression in Single Gene Diseases I
Factors Influencing Phenotypic Expression in Single Gene Diseases II
Factors Influencing Phenotypic Expression in Single Gene Diseases III
Factors Influencing Phenotypic Expression in Single Gene Diseases IV
Factors Influencing Phenotypic Expression in Single Gene Diseases V
Factors Influencing Phenotypic Expression in Single Gene Diseases VI
Factors Influencing Phenotypic Expression in Single Gene Diseases VII
Prader-Willi Syndrome
Angelman Syndrome
BC3_4
Hardy- Weinberg Equilibrium I
Hardy –Weinberg Equilibrium II
Hardy- Weinberg Equilibrium III
Factors Responsible for Genetic Variations in Populations
Natural Selection
Genetic Drift
Gene Flow
Consanguinity
BC3_5
Cytogenetics
Karyotype
Numerical Chromosome Abnormalities
Normal Meiosis
Nondisjunction During Meiosis I
Nondisjunction During Meiosis II
Structural Chromosomal Abnormalities
Reciprocal Translocation
Robertsonian Translocation
Deletion
Other Types of Structural Abnormalities I
Other Types of Structural Abnormalities II
Flourescence In Situ Hybridization (FISH)
BC4_1
Introduction
Achondroplasia
Autosomal Dominant Polycystic Kidney Disease
Familial Adenomatous Polyposis
Familial Hypercholesterolemia
Hereditary Hemorrhagic Telangiectasia
Hereditary Spherocytosis
Huntington’s Disease
Marfan Syndrome
Multiple Endocrine Neoplasia Syndromes
Neurofibromatosis
Tuberous Sclerosis
von Hippel-Lindau Disease
BC4_2
Autosomal Recessive Diseases
Cystic Fibrosis
BC4_3
X- Linked Recessive Disorders
Duchenne’s Muscular Dystrophy
BC4_4
Fragile X Syndrome
Friedreich’s Ataxia
Myotonic Dystrophy
BC4_5
Down Syndrome (Trisomy 21) I
Down Syndrome (Trisomy 21) II
Edwards Syndrome (Trisomy 18)
Patau Syndrome (Trisomy 13)
BC4_6
Cri-Du-Chat Syndrome
Williams Syndrome
Microdeletion at Chromosome 22q11
BC5_1
Introduction
Hormones: General Characteristics
Hormones Classification
Signal Transduction by Water Soluble Hormones
Trimeric G Protein
cAMP and PIP2 Systems
Atrial Natriuretic Peptide and Nitric Oxide Systems
Insulin Receptor
BC5_2
Vitamin Classification
Thiamine (B1)
Riboflavin (B2)
Niacin (B3)
Pantothenic Acid (B5)
Pyridoxine (B6)
Biotin (B7)
Folic Acid (B9)
Cobalamin (B12)
Ascorbate (Vitamin C)
Vitamin A
Vitamin A and Vision
Vitamin A Deficiency and Clinical Uses
Vitamin D
Vitamin D Deficiency
Vitamin D Toxicity
Vitamin K
Vitamin E α-Tocopherol
BC6_1
Introduction
Energy from Different Sources
Energy Storage
Levels of Metabolic Pathways Control
Metabolic Profile of the Well-Fed (Absorptive) State
Metabolic Profile of the Post-Absorptive State
Well-Fed Vs. Fasting States
Exercise Vs. Resting Skeletal Muscle
BC6_2
Overview of Carbohydrate Metabolism
Major Glucose Transporters
Insulin Regulation of Glucose
BC6_3
Introduction to Glycolysis
Glycolysis
ATP Production from Glycolysis
2,3 Biphosphoglycerate and Pyruvate Kinase Deficiency
BC6_4
Galactose Metabolism
Fructose Metabolism
BC6_5
Pyruvate Dehydrogenase
Pyruvate Dehydrogenase Deficiency
BC6_6
Citric Acid Cycle
Electron Transport Chain I
Electron Transport Chain II
Pathologies Affecting the Electron Transport Chain
Uncoupling
BC6_7
Glycogen
Glycogen Synthesis and Breakdown
Glycogen Storage Diseases
Glycogen Storage Disease Type I: Von Gierke’s Disease
Glycogen Storage Disease Type II: Pompe’s Disease
Glycogen Storage Disease Type III: Cori’s Disease
Glycogen Storage Disease Type IV: Andersen’s Disease
Glycogen Storage Disease Type V: McArdle’s Disease
Glycogen Storage Disease Type VI: Hers Disease
BC6_8
Gluconeogenesis
BC6_9
Hexose Monophosphate Shunt
Role of HMP Shunt in Hepatocytes, Phagocytes and RBCs
Glucose 6-Phosphate Dehydrogenase Deficiency
Alcohol Metabolism
BC7_1
Introduction
Fatty Acid Biosynthesis
Lipid Storage
Glycerophospholipids
BC7_2
Lipoprotein Metabolism
Classes of Lipoproteins and Important Apoproteins
Liporpotein Metabolism: Chylomicrons and VLDL
Lipoprotein Metabolism: LDL and HDL
Regulation of Cholesterol Level in Hepatocytes
LDL, HDL and Atherogenesis
BC7_3
Primary Hyperlipidemias
Hypolipidemias
BC7_4
De Novo Cholesterol Synthesis
BC7_5
Lipid Catabolism
Fatty Acid Beta Oxidation
Disorders of Beta Oxidation
Propionic Acid Pathway
BC7_6
Ketone Body Metabolism
Ketoacidosis
BC7_7
Sphingolipids
Tay-Sachs Disease
Gaucher’s Disease
Fabry’s Disease
Niemann-Pick Disease
Krabbe Disease
Metachromatic Leukodystrophy (MLD)
Genetic Deficiencies of Sphingolipid Catabolism I
Genetic Deficiencies of Sphingolipid Catabolism II
BC8_1
Introduction
Amino Group Removal for Elimination as Urea and Ammonia
Urea Cycle
Urea Cycle Disorders: Primary Hyperammonemia
Carbamoyl Phosphate Synthetase and OTC deficiencies
Urea Cycle Disorders: Arginase Deficiency
BC8_2
Genetic Disorders of Amino Acids Metabolism
Phenylketonuria and Alkaptonuria
Maple Syrup Urine Disease
Neonatal Ketoacidosis
Homocysteinuria
BC8_3
S-Adenosylmethionine
Folate Metabolism
Catecholamine Synthesis
BC8_4
Heme Synthesis
Vitamin B6 Deficiency vs. Iron Deficiency vs. Lead Poisoning
Iron Metabolism
Heme Catabolism and Bilirubin
BC9_1
Introduction
Nucleotides Synthesis and Functions
BC9_2
Pyrimidine Synthesis
Pyrimidine Synthesis: OTC Deficiency
BC9-3
De Novo Purine Synthesis
Purine Salvage Pathway I
Purine Salvage Pathway II
Nội dung
Biochemistry Molecular Biology Part I Megan Murray M.D., Ph.D Candidate University of Buffalo BC01_1- Nucleic Acid Components • DNA and RNA are assembled from nucleotides: Nitrogenous base Pentose Phosphate • • Pentoses: Ribose → RNA; Deoxyribose → DNA Nitrogenous bases: Purines: rings Pyrimidines: ring Pure As Gold •FA 2013: 64.2 • FA 2012: 68.2 • FA 2011: 67.1 • ME 3e: 60.3 • ME 4e: 60.3 CUT the pie BC01_1- BC01_1- Nucleic Acid Components • • • Nucleoside: nitrogenous base + ribose Nucleotide: nucleoside + phosphate group(s) Nucleic acids: polymers of nucleoside monophosphates Structural elements of the most common nucleotides Commons.wikimedia.org Used with permission •FA 2013: 64.2 • FA 2012: 68.2 • FA 2011: 67.1 • ME 3e: 60.3 • ME 4e: 60.3 BC01_1- BC01_1- Nucleic Acid Composition • Phosphate group links 3’ carbon of deoxyribose to 5’ carbon of another deoxyribose • Each strand has 5’ and 3’ ends • Eukaryotes DNA is double-stranded RNA is single-stranded • Strands are joined by hydrogen bonds between bases • Bases of adjoining strands are always complementary A : T, C : G (DNA) U : T, C : G (RNA) Total purines = pyrimidines • Strands are anti-parallel 5’ to 3’ •FA 2013: 64.2 • FA 2012: 68.2 • FA 2011: 67.1 • ME 3e: 60.3 • ME 4e: 60.3 BC01_1- BC01_1- Chromosome Composition • Nuclear DNA is first packaged in a nucleosome Nucleosome • Negatively charged DNA winds around positively charged histone octamer • Histone octamer: copies of H2A, H2B, H3, and H4 • Histone H1: between adjacent nucleosomes • Difference between 10nm and 30nm chromatin is presence or absence of histone H1 •FA 2013: 64.1 • FA 2012: 68.1 • FA 2011: 66.1 • ME 3e: 60.3 • ME 4e: 60.3 BC01_1- BC01_1- Chromosome Composition Euchromatin • Loosely condensed nucleosomes • Accessible for transcription Heterochromatin • Densely condensed nucleosomes • Inaccessible for transcription •FA 2013: 64.1 • FA 2012: 68.2 • FA 2011: 66.1 • ME 3e: 60.3 • ME 4e: 60.3 BC01_1- BC01_1- DNA Replication Definition • Process by which genetic information is transmitted from cell to cell Process • complementary strands of parental DNA are pulled apart • Each is used as template for synthesis of new strand • Bidirectional and semi-conservative •FA 2013: 68.1 • FA 2012: 72.1 • FA 2011: 70.1 • ME 3e: 63.1 • ME 4e: 63.1 BC01_2- BC01_2- DNA Replication Sequence of events 5’ 3’ Base sequence recognized at origin of replication 3’ 5’ Helicase Origin 5’ 3’ 3’ 5’ 3’ 5’ Leading strand 5’ 1 3’ 3’ Lagging strand 5’ 3’ 3’ 3’ 5’ 5’ Single-stranded DNA binding protein (SSB) binds to each strand Primase synthesizes RNA primer (5’→ 3’) at origin of each parental strand to be complementary and antiparallel to DNA template strands DNA polymerase (III in prokaryotes and α/δ in eukaryotes) begins DNA synthesis Leading strand: continuous and toward replication fork Lagging strand: Okasaki fragments, away from replication fork 5’ 5’ Helicase breaks hydrogen bonds holding base pairs together → unwinding begins Site of quinolones, etoposide action! 3’ RNAse H removes primers, DNA polymerase fills gaps DNA polymerase has capacity to proofread by possessing 3’-exonuclease activity DNA ligase seals nicks between Okasaki fragments Topoisomerase II (DNA gyrase) relieves strain of supercoiling Replication is completed when forks meet •FA 2013: 68.1 • FA 2012: 72.1 • FA 2011: 70.1 • ME 3e: 63.1 • ME 4e: 63.1 BC01_2- BC01_2- Telomerases Telomeres • Repetitive sequences at ends of linear DNA molecules • Replication shortens telomere length, contributing to genetic material loss and cell aging Telomerase • Enzyme which maintains telomere length (embryonic, germ, and stem cells) by replacing telomere sequences on parent strand • Inactive in somatic cells (skin, blood, connective tissue) • Prokaryotes have single circular chromosomes, hence no telomerases • Inappropriately present in cancer cells • FA 2013: NA • FA 2012: NA • FA 2011: NA • ME 3e: NA • ME 4e: NA BC01_2- BC01_2- DNA Repair 3’ Nucleotide excision repair T A 5’ T A 5’ 3’ UV • Excision endonuclease nicks the phosphodiester backbone of damaged strand 3’ • Removes defective oligonucleotide • DNA polymerase fills gap & DNA ligase seals nick 5’ T=T A 5’ A 3’ Excision endonuclease Xeroderma pigmentosum Xeroderma pigmentosum (XP) 3’ 3’ • Enzyme deficiency leads to XP 5’ T=T 5’ • Autosomal recessive 3’ A A 5’ • Extreme sensitivity to sunlight DNA polymerase Nick 3’ • Skin cancer (melanomas) 5’ T A • Diagnosis: excision endonuclease levels 5’ •FA 2013: 69.1 • FA 2012: 73.1 • FA 2011: 71.1 • ME 3e: 64.2 • ME 4e: 64.2 3’ DNA ligase • Skin freckling 5’ T A 3’ BC01_3- BC01_1- Homocysteinuria Signs and symptoms • ↑ homocysteine and methionine α -ketobutyrate • Marfanoid features + spontaneous thromboembolism Cysteine Cystathionine Cystathionine synthase CH3 THF B6 Homocysteine Homocysteine methyltransferase B12 Methionine S-Adenosylhomocysteine • Methyl groups for biosynthesis • Epinephrine • N-methylguanosine cap on mRNA ATP Pi + PPi • FA 2013: 109.1 • FA 2012: 113.1 • FA 2011: 108.3 • ME 3e: 48 • ME 4e: 48 S-Adenosylmethionine BC08_2-5 S-Adenosylmethionine Homocysteine methyl transferase N5-methyl THF B12 From diet Methionine Homocysteine S-Adenosylhomocysteine Methyl groups for biosynthesis of epinephrine N-methylguanine cap on mRNA ATP Pi + PPi • FA 2013: 109.1 • FA 2012: 113.1 • FA 2011: 108.3 • ME 3e: 47 • ME 4e: 47 S-Adenosylmethionine BC08_3-1 Folate Metabolism • FA 2013: 92.2 • FA 2012: 97.2 • FA 2011: 92.2 • ME 3e: 56 • ME 4e: 56 BC08_3-2 Catecholamine Synthesis Specific products derived from amino acids: • Tyrosine → thyroid hormones, melanin, catecholamines • Tryptophan → serotonin, NAD, NADP • Arginine → NO • Glutamate → GABA • Histidine → Histamine • Glycine → Heme • FA 2013: 108.1 • FA 2012: 112.1 • FA 2011: 107.1 • ME 3e: 46 • ME 4e: 46 BC08_3-3 Heme Synthesis • B6 deficiency → sideroblastic anemia • Iron deficiency → microcytic hypochromic anemia • Lead poisoning → microcytic sideroblastic anemia • FA 2013: 358.1 • FA 2012: 386.1 • FA 2011: 354.1 • ME 3e: 46 • ME 4e: 46 BC08_4-1 Vitamin B6 Deficiency vs Iron Deficiency vs Lead Poisoning Vitamin B6 Deficiency Iron Deficiency Lead Poisoning Microcytic Microcytic Microcytic; coarse basophilic stippling in erythrocytes Ringed sideroblasts in bone marrow - Ringed sideroblasts in bone marrow ↓ protoporphyrin ↑ protoporphyrin ↑ protoporphyrin ↓δ-ALA Normal δ-ALA ↑δ-ALA ↑ ferritin ↓ ferritin ↑ ferritin Normal serum iron ↓ serum iron ↑ serum iron Caused by isoniazid (TB) Caused by dietary iron insufficient to compensate for normal loss Caused by lead paint, pottery glaze, batteries • FA 2012: 386 • FA 2011: NA • FA 2010: NA • ME 3e: NA • ME 4e: NA • FA 2013: NA • FA 2012: 386 • FA 2011: NA • ME 3e: NA • ME 4e: NA BC08_4-2 Iron Metabolism Hemochromatosis • Mutation of HFE gene → ↑ iron absorption Ferroxidase (ceruloplasmin) • Ferritin binds iron → hemosiderin → deposits in tissues Liver cirrhosis and dermatitis Bronze skin • FA 2013: NA • FA 2012: NA • FA 2011: NA • ME 3e: NA • ME 4e: NA BC08_4-3 Heme Catabolism and Bilirubin UDP-glucuronyl transferase deficiency Kernicterus: accumulation of bilirubin in the brain (basal ganglia) • FA 2013: 358.1 • FA 2012: 386.1 • FA 2011: 354.1 • ME 3e: 46 • ME 4e: 46 BC08_4-4 Biochemistry Purines and Pyrimidines Megan Murray, M.D., Ph.D Candidate University of Buffalo Nucleotide Synthesis and Functions Nucleotide functions DNA and RNA synthesis Energy transport Nucleotide synthesis De novo synthesis (predominantly liver) Salvage pathway (peripheral cells outside the liver) • FA 2013: 65.1 • FA 2012: 69.1 • FA 2011: 67.1 • ME 3e: 60 • ME 4e: 60 BC09_1-2 Pyrimidine Synthesis • FA 2013: 65.1 • FA 2012: 69.1 • FA 2011: 67.1 • ME 3e: 61 • ME 4e: 61 BC09_2-1 Pyrimidine Synthesis: OTC Deficiency Ornithine transcarbamylase deficiency (OTC) • • • • Urea cycle Orothic aciduria Hyperammonemia No megaloblastic anemia Uridine monophosphate synthase deficiency • • • • Pyrimidine synthesis Orothic aciduria No hyperammonemia Megaloblastic anemia Pyrimidine Synthesis Pathway Urea Cycle • FA 2013: 65.2 • FA 2012: 69.2 • FA 2011: 67.2 • ME 3e: 61 • ME 4e: 61 BC09_2-2 De Novo Purine Synthesis Allopurinol 6-mercaptopurine • FA 2013: 65.1 • FA 2012: 69.1 • FA 2011: 67.1 • ME 3e: 62 • ME 4e: 62 BC09_3-1 Purine Salvage Pathway • FA 2013: 66.1 • FA 2012: 70.1 • FA 2011: 69.1 • ME 3e: 62 • ME 4e: 62 BC09_3-2 Purine Salvage Pathway Severe Combined Immunodeficiency • Lack of B- and T-cell function • Recurrent infections Allopurinol • Inhibits xanthine oxidase Hyperuricemia Adenosine deaminase deficiency • Autosomal recessive • Leads to accumulation of dATP • Orange, needle-shaped sodium urate crystals in diapers of infants • Crystal precipitation in joints induces inflammation gouty arthritis • Crystal precipitation in kidneys urate nephropathy • FA 2013: 66.1 • FA 2012: 70.1 • FA 2011: 69.1 • ME 3e: 62 • ME 4e: 62 BC09_3-3 ... 75.1 • FA 2010: 75.1 • ME 3e: 66.1 • ME 4e: 66.1 BC01_4- BC01_4- tRNA • tRNA carries activated (high energy) amino acid for translation • Each tRNA carries one activated amino acid determined... its anticodon sequence • Amino acid activation catalyzed by aminoacyl-tRNA synthetase Requires high energy bonds from ATP Transfers activated amino acid onto 3’ end of correct tRNA • tRNA has... Phase • Three-step cycle repeated for each amino acid added to protein after initiator Met • Four high energy bonds used per cycle: Two ATPs for charging tRNA and peptide bond formation Two GTPs