Collagen - Diseases
Vitamin C required to keep prolyl/lysyl hydroxylase in active form (in Fe2+ form)
Leads to Scurvy
Collagen – Inborn errors
Osteogenesis Imperfecta skeletal deformities b/o brittle bones
Defect in synthesis of Type I Collagen
(1 glycine to cysteine)
Ehlers-Danlos Syndrome hypermobile joints which frequently dislocate
(EDS) extensible skin, but bone is normal
Type VI LYSYL HYDROXYLASE deficiency
Type VII PROCOLLAGEN AMINOPEPTIDASE defect
Menkes Sydrome decreased uptake of copper => defected LYSYL OXIDASE
(kinky hair)
Lathyrism occurs when cattle eat sweet pea
Contains α-amino proprionitrile
Inhibits LYSYL OXIDASE
Marfan’s Sydrome Fibrillin mutation
Causes elongation of bones/digits/etc
Elastin
α-antitrypsin deficiency increased ELASTASE activity
Removes elastin
Lungs cannot replace elastin once damaged => emphysema
Hemoglobin
CO Bonding binds to heme group
Prevents Hb from releasing oxygen
Sickle Cell Disease structural abnormality in β-globin
Hemolytic and painful vaso-occlusive crises => pain in bones, chest and
abdomen
Mechanism cannot tolerate high protein concentrations when deoxy
Forms long filamentous polymers that readily precipitate
Mutation is Glu6β to Val (charged to hydrophobic)
Valine interacts with Phe85 & Leu88 (“sticky patch”)
Increased
resistance to malaria
Other Mutants
Structural Variants single amino acid substitutions
Frame shifts, internal deletions and chain termination mutations
Thalassemias reduced output of one or more globin chains
Plasma Proteins
Analbuminemia low levels of albumin
α-fetoprotein levels
In fetuses indicates open neural tube defect
In adults patients suffering liver cancer
Leads to Kayser-Fleischer Rings
Haptoglobulin Levels low levels in patients with HEMOLYTIC ANEMIA
Used to evaluate rheumatic disease
Transferrin (β-Globulin) increased levels lead to increased depositing of iron in tissues
Hemopexin increased levels occur in patients with:
Diabetes, Duchenne muscular dystrophy and some cancers
Mitochondrial Diseases
KSS Kears-Sayre Syndrome
Caused by Deletion
External ophthalmoplegia
Retinal degeneration
Cardiac conduction abnormalities
CEOP Chronic External Ophthalmoplegia Plus
Deletion
MELAS Mitochondrial Encephalomyopathy Lactic Acidosis & Stroke- Like Symptoms
Point Mutation in tRNA leucine
MERRF Myoclonic Epilepsy and Ragged-Red Fiber Disease
Point Mutation in tRNA lysine
LHON Lebers Hereditary Optic Neuropathy
Point
Mutation in subunit 4 of NADH
Dehydrogenase
Oxidases and Oxygenases
Mental Depression Under-activity of sertotoninergic neurons.
Previously treated with Monoamine Oxidase (MAO) inhibitors => hypertensive crises.
Now treated with serotonin re-uptake inhibitors (Prozac, Paxil)
Parkinson’s Disease Destruction of dopaminergic neurons.
Can be improved if treated with β-MAO inhibitors in early stage
Congenital Adrenal Caused by genetic defects in different mixed-function oxygenases
Hyperplasias
Alcohol and p450 Alcohol inhibits p450 monooxygenases with will increase effects of barbiturates, possibly to lethal levels.
Carbohydrate Digestion
Indigestible Carbohydrates Indigestible polysaccharides can be digested by bacteria in the lower part of the gut, which can lead to gas and the runs (e.g. Raffinose)
α-Amylase Inhibitors Originally sold as slimming aids. The starch is broken down by bacteria in gut instead and leads to same problem as above.
Lactose Intolerance Caused by a deficiency of β-Galactosidase (lactase). The lactose can be broken down by bacteria in gut and leads to same problem as above.
In babies Can occur in premature infants, because lactase enzyme not produced yet. Usually disappears.
Surgical Removal If portions of jejunum/ileum are removed, can lead to intolerance
Mucosal Cell Induced by bacteria/protozoan infection, disappears when infection
Damage is cured. (non-tropical sprue, gastroenteritis, giardia)
Adult Onset Most common form. Due to fall in lactase levels with increasing
age.
Sucrase Deficiency unable to digest sucrose. Same symptoms as indigestible carbohydrates
Monosaccharide Rare congenital disease where glucose and galactose are absorbed
Malabsorption only slowly from intestinal lumen, because of defect in absorptive transport system. Fructose is digested normally.
Glycolysis
Pyruvate Kinase Deficiency leads to hemolytic anemia
Erythrocyte is dependent on glycolysis for ATP (no
Pyruvate Dehydrogenase Complex
Enzyme 3 Deficiency also affects α-ketoglutarate Dehydrogenase and Branched Change α-ketoglutarate Dehydrogenase
Increase in α-KGDH, glutamate, and branched chain amino acids
Mutations Will cause lactic acidosis (pyruvate will not become acetyl-CoA so it will become lactic acid
Neurological Symptons:
Ataxia, Choria, Coma/Death
Retardation and Variable Optic Atrophy
Hormone Action
Cholera Covalent modification of Gsα protein => inactivation of GTP-ase activity => continuous stimulation of adenylate cyclase => high levels of cyclic AMP
Pertussis Toxin Whooping Cough
Catalyzes ADP-ribosylation of Gi protein => activation of adenylate cyclase => high levels of cyclic AMP
Glycogen Metabolism
Glycogenosis
Type I von Gierke’s disease
Deficiency
of glucose-6-phosphatase
High [glucose] in liver and renal tube
Hypoglycemia, ketosis, hyperlipemia
Type II Pompe’s disease
Deficiency
of lysosomal α-1,4 and 1,6 glucosidase (maltase)
Accumulation of glycogen in lysosomes
Fatal
Type III Limit Dextrinoses, Forbes’ or Cori’s Disease
Absence
of debranching enzyme
Accumulation of a characteristic branched polysaccharide
Type
IV Amylopectinosis,
Absence
of branching enzyme
Accumulation of a polysaccharide having few branch points
Death due to cardiac or liver failure in first year of life
Type V Myophosphorylase Deficiency, McArdle’s syndrome
Absence of MUSCLE phosphorylase
Diminished exercise tolerance;
Muscles have abnormally high glycogen content.
Little or no lactate in blood after exercise
Type VI Hers’ disease
Deficiency
of LIVER phosphorylase
High glycogen content in liver
Tendency towards hypoglycemia
Type VII Tarui’s disease
Deficiency of phosphofructokinase (PFK) in muscle and erythrocytes
Same as Type V and ALSO chance of hemolytic anemia
Type VIII Deficiency in LIVER phosphorylase kinase
Same as Type VI
Pentose Phosphate Pathway
Glucose-6-P Drug Induced Hemolytic Anemia.
DH Deficiency Caused in conjunction with primaquine (anti-malarial), aspirin,
sulfonamides or fava beans (favism)
Oxidation of NADPH => inability to keep glutathione (in RBCs) in
reduced form => RBC lyses
Lipids
Diseases
Gall Stones Occur in 20% of the Population
Cholesterol Rich Stones form in Gall Bladder
Phospholipids solubilizes cholesterol, but
Cholesterol > Phospholipids è Gall Stones (Crystallizing of Cholesterol)
Refsum’s Disease a.k.a. phytanic acid storage syndrome
Inability to do α-oxidation, so Phytanic CANNOT go to Pristanic
Demyelination because of proliferation/enlargement of Schwann Cells
Zellweger’s Synd. Bad peroxins è Bad Peroxisomal Biogenesis è Bad Peroxisomes
Death within 12 months of birth
Accumulation of VLCFAs and Pristanic Acids
Pathological Ketosis Uncontrolled Diabetes
Cannot use blood glucose so hydrolyzes fat and makes ketones
Familial LPLase Def. LPLase Deficiency
(Type I) Production of Abnormal LPLase
apoC-2 Deficiency
Pancreatitis
Familial Coronary Heart Disease
Hypercholesteremia
(Type II)
Class 1 Complete Loss of Receptor Synthesis
Class 2 LDL receptor is synthesized but NOT processed by Golgi
Class 3 Receptor is unable to bind LDL
Class 4 Receptor binds but cannot internalize
Familial Overproduction of VLDL
Hypertriglyceridemia Coronary Heart Disease
(Type IV)
Familial Combined Overproduction of apoB-100 in LIVER
Hyperlipidaemia High VLDL, IDL, LDL, TAG, Cholesterol
Wolman’s Disease Defective lysosomal cholesterol ester hydrolase
Results in reduced LDL clearance è Accumulation of Chol. Esters
Death before 6 months
Drugs
Lovastatin “Statin” Drugs
Mevastatin Reversible and Competitive Inhibitors of HMG-CoA Reductase
Control of Hypercholesterolemia
Cholestryamine Increases Bile Excretion
Nicotinic Acid Decreases Liver Secretion of VLDL
(Niacin)
Clofibrate derivatives of Fibric Acid
Gemfibrozil Active LPLase è higher VLDL turnover
Fenofibrate
Aspirin Acetylates Ser-530 & irreversibly blocks COX pathway
Membrane Transport
Paroxysmal Notcturnal Intravascular Hemolysis and Venous Thrombosis
Hemoglobinuria mutation of cell that makes GPI Anchor
Cardiac Glycosides Digitalis and Ouabain
Inhibits Na/K Pump è Inc. [Na] in heart è Inhibits Na/Ca Pump
è Inc. [Ca] in Heart è Stronger Contraction
Can be used clinically for weak hearts in moderate usage
Cystic Fibrosis ΔF508 è mutation of CFTR è Cl Transport Problem è Thick Mucus
è Inc. Susceptibility to Infection (mucus is hard to clear from throat)
Also obstruction of pancreatic duct
CFTR Structure:
2 Nucleoside Binding Folds
2 Trans-membrane spanning regions
1 Regulating Region (PKA)
DNA Packets
Diseases
α-amanitin “Mushroom Toxin”
Cyclic Octapeptide
Inhibits RNA Pol Type II Strongly and Type III Slightly
Systemic Lupus Autoimmune Disease
Erythmatosis Patients make antibodies to RNA in their “Snurps”
Corynebacterium ADP-Ribosylation of Diphthamide (Modified Histadine)
Diphtherae Inhibits EF-2 of Translation in Eukaryotes
Drugs
Acyclovir Anti-Viral Drug
Herpes Simplex I & II
Varicella Roster (Chicken Pox and Shingles)
Epstein-Barr Virus (Mononucleosis, Burkitt’s lymphoma)
NOT Cytomegalovirus
Analogue of (deoxy) guanosine
Ribose is missing bottom half è inability to elongate DNA chain
Does not affect normal cells because of normal thymidine kinase activity
Cytosine Arabinoside Ribose is Replaced by Arabinose
Anti-Cancer Drug
Toxic to Normal Cells, but MORE toxic to Cancer cells
Drug of Choice for Myoblastic Leukemia
Rifamycin Inhibits initiation of prokaryote transcription
Rifampcin
Actinomycin-D Used for Cancers
Inhibits separation of DNA strands è Inhibits Transcription (Proks, Euks)
è Inhibits DNA Replication
Puromycin Binds to the A site of ribosomes and causes premature chain termination
Affects BOTH PROKS and EUKS
Tetracyclines Prevents Aminoacly-tRNA from entering A Site in Proks AND Euks
Used Clinically because they Concentrated by PROKARYOTES
Streptomycin Prevents binding of f-met-tRNA to P Site
Also Caused Misreading of mRNA è proteins with mistakes
Bacteria can develop resistance
Chloramphenicol Prevents Peptide Bond Formation in PROKARYOTES
Cycloheximide Similar to Chloramphenicol except EUKARYOTES
Erythromycin Blocks Translocation on PROKARYOTES
Nitrogen Packets
Celiac Allergic Condition to Gliadin (wheat protein)
Inflammation of Intestinal Wall è Impairment of Nutrient Absorption
Hartnup’s Disease Involves Transport of Large NEUTRAL, AROMATIC Amino Acids
Excreted in feces in large amounts
Malabsorption of amino acids è deficiency of essential amino acids
Cystinuria Defect in kidney tubular reabsorption of Cysteine and BASIC amino acids
Kidney Stones (Cystine)
Histidemia Deficiency of Histidase
Hyperammonemia (Urea Cycle)
General Due to reduced Urea Production
TCA Cycle impaired
Brain Oxygen consumption is depleted (TCAèETC)
Deficiency In: Build Up Of: Results In:
Type I CPS – 1 CO2 & NH4
Type II OTC Carbamoyl-P Orotic Aciduria ASS Citrullinemia
ASL Argininosuccinate Aciduria
Arginase Argininemia
Hyperphenylalanemia
General High [Phe]
Defect of component in Phe Hydroxylating (PAH) System
Type I HPA Classical PKU (Phenylketonuria)
Increased ketones in urine
Severe Mental Retardation
Tyrosine becomes ESSENTIAL
Type II/III Benign
Type IV/V Lethal/Malignant
Deficiency of Dihydrobiopterin Reductase (IV)
Deficiency of Dihydrobiopterin Synthetase (V)
BH4 Deficient (Both) è Reduces synthesis of neurotransmitter
precursors, DOPA, 5-OHTrp
Treatment è BH2, BH4, DOPA, 5-OHTrp
Maternal PKU compromises growth, could cause microcephaly and mental retardation
Very high intrauterine Phe è Cross Placenta
Tyrosinemia
Albinism Deficiency of Tyrosinase
Type I Nastier
Defect in Fumarylacetoacetate Hydrolase
Build up of substrates è Hepatorenal involvement and Death
Type II Deficiency of (Hepatic) Tyrosine Aminotransferase
Benign, but optic/skin lesions because of low Phe/Tyr diet
Alkaptonuria Black Urine Disease
Defect in Homogentisic Dioxygenase
Maple Syrup Urine Branched Chain alpha-keto acid DH is absent or dysfunctional
Disease XS Branched Chain A.A.’s and Parent keto acids go in blood/urine w/
hydroxy acids
(-) TCA è Degeneration of CNS
Test for hyperleucinemia
Propionyl-CoA Defect è accumulation of Propionate (unusual ketone body) in blood
Carboxylase Lead to sever metabolic ketoacidosis
Isolated Defect/Absence of apocarboxylase
Multiple Reduced activity of 3 biotin dependent enzymes:
Acetyl-CoA-, Propiony-CoA-, & Pyruvate Carboxylase
Either deficiency: holocarboxylase synthetase (biotin can’t attach)
biotinidase (no biotin released)
Treatment Limit Propionyl-CoA Sources
Biotin Therapy
B12 Supplements
Methylmalonyl Defect because of deficiency of Apomutase OR AdoCbl
CoA Mutase
B12 Deficiency Very Rare in Western society
Causes Megaloblastic Anemia
SCD (Subacute Combined Degeneration)
Demyelinization
Pernicious Anemia Lack of Intrinsic Factor
Homocysteinuria Deficiency of cystathionine beta-synthase
Defect in homocysteine è methionine
Cysteine may become ESSENTIAL
Mental Retardation
Vascular Disease, Thrombosis
Stroke, MI, & Alzheimer’s
Treatment High Doses of B6, B12, Folate, Methionine
Hereditary Orotic Component of UMP Synthase is defected
Aciduria Build up of Glu, CO2
Normal Purine Synthesis cannot occur è no normal growth
Megaloblastic Anemia
Treatment Uridine absorbed orally which bypasses UMP Synthase step
Hyperuricemia Elevated Plasma [Urate]
Lead to Precipitation/Crystallization è Kidney Stones/Gout
Arise from: overproduction of urea or defected renal elimination
Metabolic Abnormailities
Incr. PRPP Increased Urate è Gout
Incr. PRPP Synth. Increased Purine Biosynthesis & Increased Urate Secretion
Von Gierke’s Glc-6-Pase deficiency
PRPP is made via PPP, so G6P defect è Inc. [PRPP]
Salvage Pathway (absence/def of HGPRT)
Partial HGPRT def. reduces purine salvage è increase free purines è inc. urate
Increase of de novo synthesis è inc. purines è inc. urate
Lesch-Nyhan overproduction of purines
Self-mutilation & mental retardation
Hyperuricemia
Gout Hyperuricemia & recurrent acute arthritis
Impaired excretion of uric acid
Urate crystals precipitate (esp. in joints of extremities)
Macrophages eat crystals è damages lysosomes è lysing of lysosome
Lysing è Inflammatory response
Treatment Non-steriodal inflammatory drugs – indomethacin
NO Aspirin because inhibits urate excretion
Colchicines - no effect on purine metabolism, prevents crystal ingestion
Heme
Porphyrias defects
in any of the enzymes:
Overproduction, accumulation, and excretion of intermediates
above block
Colored urine, stained teeth because they are oxidized by light
Neuropathy, confusion, psychosis
Hepatic Acute Intermittent porphyria
Deficiency of hepatic porpobilinogen deaminase
Porpobilinogen
and
neuropsychiatric
Four TIMES more common in FEMALES
Erythropoeitic Deficiency of Uroporphyrinogen III Cosynthase
Uroporphyrinogen I spontaneously forms
Photosensitivity & Disfigurement
Treatment Porphyrin derivatives activated by red laser light è cytotoxic
radicals
Ferrochelatase
Jaundice Not a disease
Yellow pigmentation of skin/sclera because of inc. plasma bilirubin
Pre-Hepatic Increased erythrocyte breakdown è Inc bilirubin
UNCONJUGATED bilirubin
Hepatic Failure in conjugating mechanism
UNCONJUGATED
Due to acetaminophen poisoning, viral hepatitis
Post-Hepatic Blockage of Biliary Tract (Gall stone)
CONJUGATED
Neonatal Hepatic glucuronyl transferase + ligandin system may not be mature
Cannot conjugate ALL bilirubin
If prenatal, high unconjugated bilirubin can saturate albumin
Motor disorder, mental handicap or death
Treatment Phototherapy (Blue Light) è converts bilirubin to water soluble
Bilirubin
Gilbert’s disease Defective bilirubin uptake UNCONJUGATED
Crigler-Najjar Absense of Glucuronyl Transferase UNCONJUGATED
Dubin-Johnson Syn, Defective Hepatic Secretion CONJUGATED
SCID Severe Combined Immunodeficiency
“Bubble Boy” Disease
Inherited defect in B & T Lymphocytes due to def. interleukin receptors
Adenosine Deaminase Deficiency è Inhibits DNA Syntheses
Treatment Regular Infusion of PEG-ADA
Bone Marrow Transplant
Stem Cell Transplant