Block 1 Clinical Correlates/Diseases

Hemoglobinopathies

genetic disorders cause by defective Hb

Sickle Cell (Hemogobinopathies)

results from a point mutation in B-chain gene, Glutamic Acid is replaced by Valine. Results in hydrophobic aggregates and rbc breakdown. Can be trerated with hydroxyurea (induces synthesis of HbF)

Hb Thalassemias (Hemogobinopathies)

Glutamic acid replaced by lysine

Hb Hammersmith (Hemogobinopathies)

phenylalanine replaced by serine

Hb Savannah (Hemogobinopathies)

Glycine replaced by valine

Hb Milwaulkee (Hemogobinopathies)

valine replaced by glutamic acid

Hb reduction mutant (methemoglobinema)

Fe2+ oxidized to Ferric forming methemoglobin, this is reduced back to hemoglobin by NADHihmethemoglobin reductase. defeciency in this enzyme results in methemoglobinema (APPEAR BLUE).

Thalassemias

Imbalance of globin chains

a-thalassemias

deletion of 1+ a-globin (normally 4)

B-thalassemias (minor)

single copy defective (2 copies normally)

B-thalassemias (major)

both copies defective (2 copies normally)

Protein folding disease examples

Huintingtons, Parkinsons, Alzheimers, Cystic Fibrosis, Sickle Cell.

Kwashiorkor syndrome

not enough amino acids but enough calories in diet (high carb diet and low in proteins after weened off of breast milk is a common occurance)

Marasmus syndrome

not enough amino acids or calories in diet (low access to food, often in children and the elderly and results in muscle wasting)

Scurvy

Occurs due to vitamin C definciency (co-factor for hydroxylation of proline and lysine in collagen formation. Results in poor wound healing, weak skin and blood vessels.

Ehlers Danlos Syndrome (EDS)

can be autosomal dominant or recessive, affect connective tissue by mutations in genes or defective enzymes, result in weak bones and muscles, hypermobility, and easily bruised. Occurs in steps 6 and 7 of collagen synthesis (collagen peptidases cleaving disulfide rich areas and lysyl oxidase cross-linking collagen).

Osteogenesis imperfecta (OI)

imperfect bone formation (brittle bone disease), easily fractured and bent. The glycine in type 1 collagen is replaced by a bulky aa side chain (usually step 3).

Type 1 OI

infancy with fractures due to trauma

Type 2 OI

fetus dies of pulmonary hypoplasia in utero

Type 3 OI

severe condition: spinal curve, short stature, many fractures.

Stickler Syndrome

multiple collagen gene mutations, problems with joints, distinct facial features (flat face and cleft pallet), myopia, and hearing loss.

menkes disease

deficient in Cu (co-factor for lysyl oxidase) in collagen cross-linking.

Alport syndrome

a genetic disorder characterized by progressive kidney disease, hearing loss, and eye abnormalities, caused by mutations in genes that code for type IV collagen, a critical component of the body's basement membranes

Goodpasture Syndrome

rare, serious autoimmune disorder where the immune system attacks the lungs and kidneys by targeting the basement membrane in these organs, leading to organ damage and failure if not treated quickly (type IV collagen)

osteolathyrism

toxic osteoathrogens inhibit lysyl oxidase

Marfan syndrome

Mutation in FBN1 gene

Emphysema

elastase inhibitor (AAT) is defiecient. AAT: blocks the action of elastase, a proteolytic enzyme that breaks down elastin and other proteins, thereby preventing tissue damage in diseases like emphysema and inflammation

Valinomycin

antibiotic produced by streptomyces fuluissimus. carrier of monocovalent cations, raises [K+] in mitochondira, reducing the rate of ATP Synth.

Rotenone (incectiside) and amytal (CNS depressant)

complex 1 of ETC inhibitors

Cyanide

Complex 4 of ETC inhibitor, treated by thiosulfate or nitrate, covert and inhibit respectively.

Thermogenin

forms an H+ conductive membrane with heat (endogeneous uncoupler).

Brown Adipose Tissues

prod. heat, uncouples H+ gradient with ATP Synthase for thermogenesis.

ATP/ADP Translocase

exchange ATP in matrix for cytosol, Atractyloside and bongkrekic acid: inhibit ATP/ADP exchange and reduces rate of oxidative phosphorylaytion and cellular respiration.

Arsenic Poisoning

Arsenate is incorporated into step 6 of Glycolysis, leading to no ATP production in step 7, lack of mitochondria menas no ophos and etc production of atp.

Flouride inhibition of enolase

Step 9 of glycolysis, reduced lactate production by mouth bacteria equating reduced dental cavities with flouride inhibition.

Pyruvate Kinase Deficiency

recessive mutation, 50% less ATP produced, and causes hemolytin anemia (rbcs rely entirely on glycolysis for atp)

Transcription regulated enyzmes

estrogen (ER), proesterone (PR), and thyroid (TR)

Mucopolysaccharides (GAG) Disease (Hurler syndrome MPS 1, Hunter Syndrome MPS 2, Sanfilippo Syndrome MPS 3, Sly Syndrome MPS 7)

a group of rare, inherited genetic disorders where the body lacks or doesn't have enough enzymes to break down complex sugar molecules called glycosaminoglycans (GAGs)

I-cell disease- glycoprotein synth. deficiency

certain lysosomal digestive enzymes fail to target lysosome.

Digestional Enzyme defiecientcy

hereditary, intestinal disease. results in malnutrition, can be caused by drugs that injur mucosa

Lactose intolerance (conginital lactose deficiency)

65% of the population have reduced ability to digest lactose after infancy, cause unknown. Low level of lactose (genetic change with age) or intestinal injury? Can be treated by Ca2+ consumption or lactose pill/ lactose treated products.

Sucrose-isomaltase deficiency

from a single protein, splits sucrose and maltose, intolerance to ingested sucrose, treatmeants: withold sucrose or enzyme replacement.

Fructose Intolerance (Glut5 fructose transporter deficiency)

metabloized by bacteria (GI distress), different from inability to metabolize.

asprin

suicide inhibition of prostaglandin synthease for prostaglandin and thromboxone

HMG-CoA Reductase

physiological substrate for the rate limiting step of cholesterol biosynthesis

gleevec

noncompetitive inhibitor for the treatment of leukemias

cholestasis

blocked flow of bile

Increased serum of alkaline phosphatase, ALT, and AST

Liver damage

Increased serum of ALT, AST, Aldolase, and Creatine Kinase.

Muscle Damage

Elevated secretion of serum amylase

Pancreas Damage

Elevated LDH 2 and 3 (HHHM and HHMM)

acute leukemia

Elevated LDH 1

heart

Elevated LDH 4

Liver and Muscle (anerobic)

Elevated LDH 5

Liver disease

Markers for Myocardial Infarction

CK-2, troponin I, and cardiac tropin T.

Ischemia

decreased oxygen flow to tissues resulting in damage.

Glycosaminoglycans

lubricate joints, viscous, (-) charge, repetitive units

Glycoproteins

non-repeating units, contain oligosaccharides, branched (protein>carb)

proteoglycans

membrane bound receptors, golgi synthesis, (carbs>protein).

Mouth digestional enzymes

glycosidase or glycoside hydrolase

salivary digestion enzymes

alpha-amylase (flouride inhibited)

small intestine digestion enzymes

disaccharides converted to free sugars, lactase, sucrase, maltase.

insoluble dietary fibers

cellulose, hemicellulose, ligins

soluble dietary fibers

pectins, plant gums, mucilages

dietary fiber function

lower cholesterol

osmotic pressure change results in

diarrhea

gas release due to bacterial breakdown of carbs in the colon

flatulance

How to diagnosis carbohydrate digestion deficiency

Hydrogen gas level in breath

PDH Complex E1 deficiency

results in congenitial lactic acidosis, overuse of LDH, brain is sensative to the (X-linked genetics), no proven treatment.

arsenic poisioning

inhibits lipoic acid requiring enzymes, including PDH E2, and alpha-ketoglutarate dehydrogenase, forms a stable complex with lipoic acid’s thio group, causes neurologicla disturbance and death.

Leigh Syndromes

30 different gene mutations, PDH deficiency, Pyruvate carboxylase deficiency; lactic acidema=neurological damages and respiratory failure.

Beriberi disease and Wernick-Korsakoff syndromes

thiamine (TPP) (Vitamin B1) deficiency, cofactor of E1 of PDH and alpha-ketoglutarate dehydrogenase.

hemolytic anemia

G6PDH deficiency, rbcs deicient in this result in damaged Hb (hemolysis), occurs in10% of African Males, lowered enzyme activity, fatal in embryotic stage. (Lower G6PDH means less oxidation for detoxification).

Pompe Disease (Type 2 glycogen storage disease)

glycogen accumulation is abnormal, impairs normal function. e.g., massive cardiomegely (enlarged heart and heart failure and death in infants).

Von Gierke Disease (Type 1a and 1b)

cannot release glucose to the blood, resulting in glucose accumulation in the liver and kidneys, Type 1a is deficient in G6Pase (deficient in synthesis) type 1b is deficient in G6Ptranslocase (deficient in transportation).

Fructosuria

deficiency in furctokinase, begnine

Hereditary fructose intolerance (HFI)

aldolase B deficiency, accumulation of fructose & f1p, lowers cellular inorganic phosphate

retinopathy, periphial neropathy, or neuropathy, as a result of cataract formation

excess glc leading to sorbitol accumulation

nalidixic acid/ciprofloxacin

target prokaryotic exclusive DNA Enzyme (DNA gyrase)

Antibiotics that target bacterial protein synthesis

2nd most common type of antibiotic

Aminoglycosides

streptomycin, tobramycin, gentamicin (bind 30S ribosome and cause misreading of mRNA)

Tetracyclines

bind 30S ribosome and block tRNA

macrolides

Erythromycin and Azithromycin (bind 50S and prevent peptide bonds)

chloramphenicol

bind to 50S ribosome and prevent peptide bonding