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Integrated 4 - Biochemistry - no ethanol metabolism

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d-aminolevulinic acid synthatse (ALAS)
Succinyl-CoA + Glycine --> ALA - enzyme
X-linked sideroblastic anemia
Succinyl-CoA + Glycine --> ALA - disorder
PBG deaminase
PBG --> hydroxymethylbilane enzyme
ALA dehydratase deficient porphyria
ALA --> Porphobilinogen (PBG) disorder
ALA dehydratase (PBG synthase)
ALA --> Porphobilinogen (PBG) enzyme
acute intermittent porphyria
PBG --> hydroxymethylbilane disorder
uroporphyrinogen III synthase
hydroxymethylbilane --> uroporphyriogen III enzyme
congenital erythropoietic porphyria
hydroxymethylbilane --> uroporphyriogen III disorder
uroporphyrinogne decarboxylase
uroporphyriogen III --> coproporphyrinogen III enzyme
porphyria cutanea tarda
uroporphyriogen III --> coproporphyrinogen III disorder
coproporphyrinogen oxidase
coproporphyrinogen III --> protoporphyrinogen IX enzyme
hereditary coproporphyria
coproporphyrinogen III --> protoporphyrinogen IX disorder
protoporphyrinogen oxidase
protoporphyrinogen IX --> protoporphyrin IX enzyme
variegate porphyria
protoporphyrinogen IX --> protoporphyrin IX disorder
ferrochelatase
protoporphyrin IX --> Heme B enzyme
erythropoietic protoporphyria
protoporphyrin IX --> Heme B disorder
heme
the feedback inhibitor for dALA synthase activity
heme oxygenase
enzyme used to degrade heme to carbon monoxide, biliverdin and iron
bilirubin
most abundant antioxidant in the body.
Can bind albumin.
Cleared via GI and Renal tracts
Overproduction can promote kernicterus.
Insoluble until conjugated with glucuronic acid.
Acute bilirubin encephalopathy (ABE)
symptoms include lethargy, irritability, generally reversible
Chronic bilirubin encephalopathy (CBE)
symptoms include severe neural deposits, motor impairments, oculomotor impariemnts
Subtle bilirubin encephalopathy (SBE)
symptoms include mild bilirubin-induced neurological dysfunction.
Gilbert syndrome
Autosomal dominant trait
Reduced activity of the enzyme glucuronyltransferase which conjugates bilirubin
Usually occurs after puberty
No treatment required.
porphyria
diosrder that limits heme syhteiss and increases concentration of dALA
dALA
structurally related to gluatmate so it can bind to its receptors.
Build up leads to symptoms of porphyria and nerve damage.
Acute Porphyrias
Acute intermittent porphyria
Aminolevulinic acid dehydratase deficiency porphyria
Hereditary coproporphyria
Variegate porphyria
Cutaneous Porphyrias (chronic nature)
Erythropoietic porphyria
Congenital erythropoietic porphyria
Porphyria cutanea tarda
Acute intermittent porphyria (AIP)
Autosomal dominant disorder
Impairment of PBG deaminase
Chronic skin and neural problems
TRIGGERED BY EVENTS DRIVING dALA SYNTHASE
"Classic" porphyria
Symptoms of AIP
Abdominal and/or back pain.
Exaggerated symptoms of peripheral neuropathies
Intense nausea
Confusion, light headedness.
General sense of alarm (feeling of dying)
Signs of sympathetic discharge.
Congenital Erythropoietic Porphyria (aka Gunthers Disease)
X-Linked autosomal recessive disorder
Impairment of uroporphyrinogen synthase
Hydroxymethylbilane accumulates (ferocious pink)
Profound skin lesions and disfigurement
Only girls get it
Porphyria Cutanea Tarda
Autosomal dominant disorder
Impairment of uroporphyrinogen decarboxylase
Neural and skin problems.
Uroporphyrinogen accumulates
Extreme photosensitivity
Hereditary Coproporphyria
Autosomal dominant disorder
Impairment of coproporphyrinogen oxidase
Mild neural and skin problems
Coproporphyrinogen accumulates
Photosensitivity (erythema, bullae milia)
Erythropoietic Protoporphyria
Autosomal dominant
Slow heme turnover due to slow ferrochelatase
Protoporphyrin IX accumulates
Mostly dermal effects.
Photosensitivity, itching, redness, painful erosions.
Ceruloplasmin
binds copper; appears to be more important as copper storage pool than as a transport protein; integrates iron and copper homeostasis
Haptoglobin
binds extracopuscular hemoglobin
transferrin
transports iron
Hepcidin
main regulator of iron transport as an inhibitor.
Low levels lead to iron absorption and transport out of cell
Increased expression lead to decrease iron absorption and release from cell.
It binds to ferroportin and does not let iron release from the cell.
erythropoietin and hypoxia
these molecules decrease the expression of hepcidin leading to increse iron transport out of cell
HJV, HFE, TtR2
mutations in these will lead to too little hepcidin expressed causing too much iron to be absorbed.
Iron deficiency anemia (IDA)
Caused by inadequate dietary iron, impaired iron absorption, bleeding, or loss of body iron in the urine.
Treated with diet, oral ferrous iron salts coupled with vitamin C.
Fatigue from effect on hemoglobin, TCA, and ETC heme and iron-sulfur proteins.
liver
the primary organ that accumulates iron.
hemosiderosis
increased iron deposition in tissues from iron overload
hemochromatosis (HC)
tissue damage from excess iron
iron intoxication signs
vomiting, severe gastroenteritis, melena, hematemesis
hereditary hemochromatosis
Autosomal recessive
Mutations in the HFE gene, typically C282Y homozygotes.
No mechanism for excretion of iron.
Advanced symptoms include Hepatomegaly, skin bronzing, diabetes mellitus (bronze diabetes), severe fatigue, arthritis
ferritin
main cellular storage protein for iron.
elevated serum ferritin
This can represent iron overload but can reflect inflammation, several types of liver damage, renal disease.
decreased serum ferritin
associated with iron deficiency and hemodialysis
iron over load treatments
phlebotomy
chelation therapy
Avoid red-meat and alcohol
avoid vitamin C supplemetns or iron supplements.
Serum Iron (SI)
measures iron concentration in serum, i.e. outside of RBC
Serum Ferritin (SF)
measure of iron contained or stored in the body
Total Iron Binding Capacity (TIBC)
determines the capacity of circulating transferrin
Transferrin-iron saturation percentage (TS%)
how much of the transferrin is actually carrying iron. Normally 25-35%. Higher is suggestive of hemochromatosis. Lower is suggestive of iron deficiency anemia.
Wilson's disease
Monogenic, autosomal recessive condition involving liver sirrhosis pluss neurological and psychiatric defects.
Defects in ATP7B protein blocks copper elimination leads to Cu accumulation.
Ceruloplasmin
carries most copper in human plasma. Low serum concentrations in patients with Menkes and Wilson's disease.
Menkes (kinky hair syndrome)
ATP7A defect
X-Linked
Plasma [catechol] are abnormal due to Cu deficiency.
Low serum copper and ceruloplasmin
Suspected in males who develop hypotonia, failure to thrive, and seizures between 6-10 weeks. Hair and skin changes, neurodevelopmental delays, temperature instability, hypoglycemia. Death usually by 3.
Superoxide anion
produced by the ETC. Cannot diffuse from site of origin
Generates other reactive oxygen species
Hydrogen peroxide
not a free radical but can generat free radicals by reaction with transition metals. Can diffuse through membranes
Hydroxyl radical
the most reactive species in attacking biologic molecules. Produced from hydrogen peroxide in the fenton reaction in the presence of Cu or Fe.
Nitric Oxide
Reactive nitrogen oxygen species. A free radical that is produced endogenously by nitric oxide synthase.
Binds to metal ions.
Combines with O2 or other oxygen containing radicals to produce additional RNOS.
Haber-Weiss Reaction
Superoxide + Hydrogen peroxide --> Oxygen + water + hydroxyl radical
Fenton reaction
hydrogen peroxide --> hydroxyl radiacla and hydroxide ion
oxidases
enzymes that produce hydrogen peroxide
oxygenases
enzymes that incorporate (one or two) O2 into the substrate.
malondialdehyde
product of unsaturated fatty acid oxidation and a standard marker for oxidative stress.
CoQH
converts O2 to superoxide
NADPH
This molecule is needed to convert peroxides to water
Glutothione reductase
utilizes NADPH from the pentose phosphate pathway.
dietary antioxidants
B-carotene
lycopene
Vitamin A,C,E
N-acetyl cysteine
Melatonin
Vitamin E
terminates free radical lipid peroxidation.
Vitamin C
a reducing agent that possibly plays a role in reducing Vitamin E.
NADPH oxidases
produce superoxide from O2 and NADPH
Cytochrome P450
can transfer electrons to various oxygen species to produce ROS
Xanthine oxidase
produce superoxide and hydrogen peroxide from O2 and second substrate like xanthine or hypoxanthine
Nitric oxide synthase (NOS)
produces NO which reacts with superoxide to produce peroxynitrite
superoxide dismutase
dismutation of superoxide to oxygen and hydrogen peroxide. Deficiency in this causes ALS
Catalase
decomposition of hydrogen peroxide to water
glutothione peroxidase
reduce free hydrogen peroxide to water and lipid hydroperoxides to their corresponding alcohols.
paraoxonase (PON1)
accounts for cardioprotective and anti-atherogenic HDL function.
Deficiency causes HDL particles to become oxidized.
ischemia-reperfusion injruy
the most common cause of death in patients with cardiovascular disease.
Causes rapid build up of ROS and cell death.