Protein Synthesis:

Hutchinson-Gilford Progeria Syndrome

- GGC to GGT codon 608 of lamin A gene

- This change should be silent because they both code for glycine

- Activation of cryptic splice site results in truncated lamin A with an internal deletion of 50 amino acids

- Accumulates farnesyl and obstructs nuclear envelope

- Disrupts transcription and translation

- Premature aging- Failure to thrive and localized

scleroderma-like skin condition- Full body alopecia

Diphtheria Toxin - Endotoxin synthesized by a bacteriophage

o B subunit binds a cell surface receptor facilitating the entry of the A subunit to host Cell

o A subunit catalyzes the ADP ribosylation of EF2 to inhibit protein synthesis

- Pharyngitis, fever, swelling of the neck, and swollen skin lesions

Inhibitor EffectActing only on bacteria

Streptomycin Prevents the transition from initiation complex to chain elongating ribosome and also causes miscoding

Tetracycline Blocks binding of aminoacyl-tRNA to A-site of ribosome

Erythromycin Blocks the translocation reaction on ribosomes

Chloramphenicol Blocks the peptidyl transferase reaction on ribosomes

Acting on bacteria and eukaryotesPuromycin Causes the premature release of nascent

polypeptide chains by its addition to growin chain end

Actinomycin D Binds to DNA and blocks RNA polymerase

Liddle Syndrome - Mutation in a subunit of the renal epithelium sodium channel that interferes with binding to its E3 ligase.

- Accumulation of channel protein results in excessive Na+ resorption

- Hypertension- Abnormal kidney function

Autosomal Recessive Juvenile Parkinsonism

Mutation in the gene coding for protein ParkinParkin is a ubiquitin E3 enzyme and results in the accumulation of Parkin substrates such as alpha synuclein, a protein implicated in neuronal vesicle traffickingAlzheimers

I-Cell disease (Mucolipidosis Type II) - Intracellular inclusions- Lysosomal proteins not sorted

properly in Golgi- Defects due to mutation in the

enzyme N-acetylglucosamine phosphotransferase required for attaching mannose-6-phosphate

- Lysosome clogs - High prominent forehead,

flattened nose, narrow chest, slow development

- Early death 8 years due to recurrent respiratory infections and congested heart failure

Glycogen Storage Diseases

GSD 1: Glucose 6-Phosphatase Deficiency

Von Gierke Disease

- In liver blocks the final steps of glycogenolytic and gluconeogenic pathways

o Type 1A G6Pase catalytic activity

o Type 1B and 1C defect in translocase (transporter)

o Type 1D microsomal GLUT7 deficiency

- Impairs ability of liver to produce free glucose from glycogen and from gluconeogenesis

- Hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia

- Doll like faces and protuberant abdomen (Hepatomegaly and enlarged kidneys)

GSD 2: Lysosomal alpha-glucosidasePompe Disease

- Glycogen deposites accumulate in lysosomes

- Damage in muscle and nerves cells

- Accumulation of glycogen in the lysosome due to the deficiency of lysosomal alpha-glucosidase enzyme

- Infantile: Muscle hypotonia, cardiac failure

- Adult: limb-gridle, muscular dystrophy-like features

- Progressive accumulation causes inflammation, fibrosis, and disruption of contractile elements of muscle

- Floppy baby

GSD 3: Debrancher DeficiencyCori or Forbes Disease

- Amylo-1,6-glucosidase- Glycogen deposits have short

outer brancheso A (liver muscle)o B (liver)o C (muscle)

- Fasting ketotic hypoglycemia, hepatomegaly, short stature, variable skeletal myopathy, and hyperthrophic cardiomyopathy

- Kidneys not enlarged

GSD 5: Muscle Phosphorylase Deficiency

- Muscle phosphorylase deficiency (removes

McArdle Disease 1,4glycosyl residues from outer branches of glycogen and adds P to form G-1P)

- Exercise intolerance with muscle cramps

- Coca Cola urine due to rhabdomyolysis

-

GSD 6: Liver Phosphorylase Deficiency

Hers Disease

- Either phosphorylase b kinase deficiency or protein kinase a

- Hepatomegaly, mild hypoglycemia - Growth retardation- Glucose does not increase

following glucagon-

GSD 7: Muscle Phosphofructokinase Deficiency

Tarui Disease

-

- Severe muscle cramps- Myoglobinuria - Hemolytic anemia

GSD 11: Fanconi-Bickel Syndrome - Defects in the facilitative glucose transporter GLUT2 which transports glucose in and out hepatocytes, pancreatic B cells, and basolateral memabranes of intestinal and renal epithelial cells

- Proximal renal tubular dysfunction, impaired glucose and galactose utilization and accumulation of glycogen in liver and kidneys

- Failure to thrive protuberant abdomen (hepato and reno megaly)

- Fat deposition in shoulders and abdomen

- Osteopenia

Glycogenesis

GSD 0: Liver Glycogen Synthase Deficiency

-

- Hypoglycemia and hyperketonemia

- No hepatomegaly or hyperlipidemia

- Rise in blood lactate

GSD 4: Branching Enzyme DeficiencyAmylopectinosis or Andersen

Disease

-

- Failure to thrive- Hepatosplenomegaly- Cirrhosis- Myopathy (cardio)

Congenital Disorders of Glycosylation

CDG 1A: N-glycosylation - A- deficiency of phosphomannomutase which converts mannose-6-p to mannose-1-P

- Inverted nipples- Abnormal deposition of fat pads

CDG 1B: N-glycosylation - Phosphomannose isomerase deficiency

- Chronic diarrhea and cyclic vomiting leading to failure to thrive

- Hypoglycemia with abnormal high insulin levels

- Treated with mannose

Glycolisis Inhibitors

Inhibitor EffectDeoxy-beta-D-glucoseIodoacetate/methyl mercuric chloride

GAPDH

Fluoride EnolaseArsenate Competes with Pi for 1,3-BPG formation,

and produces less ATPArsenite Forms stable complex with enzyme

bound lipoic acid

Lysosomal Storage Diseases

Fabry’s Disease - Alpha-galactosidase A deficiency

- Accumulation of globotriasulceramide (GL-3)

- Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease

Gaucher’s Disease - Glucocerebrosidase deficiency leads to macrophage engorgement

- Hepatosplenomegaly, asepatic necrosis of femur, bone crises, Gaucher’s cells (macrophages that look like crumpled tissure paper)

- Symptoms are usually multisystemic, often debilitating or disabling, sometimes disfiguring, and can lead to death.

Niemann-Pick Disease - Sphingomyelinase- Progressive neurodegeneration,

hepatosplenomegaly, cherry-red spot on macula, foam cells

Tay-Sachs Disease - Hexosaminidase- Progressive neurodegeneration,

developmental delay, cherry-red spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs. Niemann-Pick)

Krabbe’s Disease - Galactocerebrosidase- Peripheral neuropathy,

developmental delay, optic atrophy, globoid cells

Metachromatic Leukodystrophy - Arylsulfatase A

- Central and peripheral demyelination with ataxia, dementia

Hurler’s Syndrome MPS1 - Alpha-L-iduronidase enzyme deficiency

- Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly

- Carpal tunnel syndrome (claw hands), skeletal deformities

Hunter’s Syndrome MPS2 - Iduronate-2-sulfatase enzyme deficiency

- Accumulation of glycosaminoglycans (GAG)

- Mild Hurler’s + aggressive behavior, no corneal clouding

- Bone dysplasia, cognitive impairment, cardiac disease, frequent pulmonary problems, hepatosplenomegaly