Biochem - Metabolic Diseases

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G6P DH

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1st step of pentose phosphate pathway (PPP)

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PPP purpose

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Generate NADPH to take oxidized glutathione (GSSG) -> reduced version (GSH)
- Primarily to help relieve stress from ROS in RBC's

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Glutathione-based removal of ROS

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2 GSH + ROOH -> GSSG + ROH + H2O

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Glutathione regeneration

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GSSH + 2 NADPH -> 2GSH + 2NADP+

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G6P DH deficiency

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Most common enzymopathy (mutation) in the world
- Primarily affects RBC's - PPP is only way for them to generate NADPH
- Other cells make NADPH lots of other ways

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G6P DH deficiency pathogenesis

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G6P DH mutation - becomes more unstable
- Shorter 1/2 life, ROS levels increase
- RBC's die earlier from toxic ROS action

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G6P manifestation

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Typically noticed when ROS levels increase for some reason
1) Maternal exposure to mothballs (napthalene) - oxidative compound, get neonatal jaundice
2) Acute hemolytic anemia from (oxidative) malaria drugs (Primaquine)
3) Infection (Hep A)
4) Too many fava, lima beans...favaism...

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G6P DH deficiency inheritance

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X-linked recessive
- Predominantly male patients

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Lactose intolerance

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Congenital (rare) or developed (predominant)
- Normally, Lactose -> Glucose + Galactose (Lactase)
- Loss of lactase production/function

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Lactose intolerance pathogenesis

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Lactose goes thru gut to colon
- Microbes break it down - methane gas, etc.
- Osmotic effect - diarrhea

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Lactose intolerance Rx

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Lactase supplement
- Good example of enzyme replacement therapy...

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Galactosemia presentation

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Cataracts in infants - think GALT problems
- Jaundice
- Hepatomeagaly
- Hypoglycemia

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Galactosemia pathogenesis

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GALT enzyme problem
- UDP-glucose + Galac-1P -> UDP-galac + Gluc-1P
- Pi locked up in Galac-1P
- Lack of phoshpate -> lack of ATP in liver -> No gluconeogenesis
- Galac-1P -> galacitol, accumulates in lens -> cataracts

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Hereditary fructose intolerance

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Aldolase B problem
- Usually catalyzes Fructose-1P -> Glyceraldehyde + DHAP
- Stuck at Fructose-1P

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Hereditary fructose intolerance pathogenesis

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Phosphate stuck in Fructose-1P
- Reduced ATP production, reduced gluconeogenesis
- Hypoglycemia
- Very minor fructosuria (fructose in urine) - reducing sugar!

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Increased uricemia

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Higher uric acid
- Fructose -> F-1P uses ATP -> ADP
- Increased ADP -> increased AMP
- Increased AMP -> increased IMP, NH3 byproduct

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Essential fructosuria

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Tons of fructose in urine
- Lack of fructokinase A or C
- Can't make fructose -> Fructose-1P
- Fructose cleared from body
- Symptoms result from kidney clearance issues

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Essential fructosuria C

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No fructokinase C (liver)
- Relatively benign, just clear fructose via kidneys

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Essential fructosuria A

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Rare, but bad...
- No fructokinase A in rest of body
- Liver gets overwhelmed, looks like Aldolase B defect

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IV solutions & fructose

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Fructose is NEVER in IV solutions - wipes out hepatocyte ATP stores, kills patients

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Lactic acidosis

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Basically caused by anything that messes with mitochondria
- Lack of ox. phos. -> tissues need to do glycolysis, make lactate

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Mito affecting chemicals

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Metformin - affects complex I of ETC
- Cyanide and CO also bind ETC complexes

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Lactic acidosis presentation

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Anion gap higher than 12ish
- pH less than 7.3 (7.4 = normal)

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Lactic acidosis causes

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Problems with either Pyruvate DH or ETC

Lactic acidosis due to Pyruvate DH problems;Lactate/pyruvate ratio is low
- Lactate, pyruvate levels about the same - PDH can't take pyruvate to AcoA

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Lactic acidosis due to ETC problems

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Lactate/pyruvate ratio much higher
- Pyruvate being processed, lactate building up for some other reason

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Ketoacidosis presentation

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Like lactic acidosis
- low pH, increased anion gap

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Ketoacidosis causes

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Usually Type I diabetes
- Uncontrolled lipolysis, FA oxidation in liver
- Increased AcoA -> ketone bodies

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Normal insulin FA oxidation control

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Insulin dephosphorylates (activates) AcoA carboxylase
AcoA -> malonyl-coA
- Malonyl-coA inhibits FA oxidation by blocking intake at CPT-1

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Ketoacidosis pathogenesis

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No insulin control over lipolysis, FA oxidation
- end up with excess ketone bodies, ketoacidosis

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Medium chain acyl-coA DH deficiency (MCAD) presentation

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Low blood glucose, low ketone bodies
- Not diabetes (normal glucose)
- Not FA oxidation problem (normal ketone bodies)

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MCAD pathogenesis

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MCA-coA DH not working
- Accumulation of MC fatty acyl-coA esters
- No ketone bodies, metabolic intermediates for ox. phos. being produced
- coA trapped - inhibits CAC, ox phos, and gluconeogenesis

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MCAD treatment

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Immediate carnitine supplements, intravenous glucose
- Low-fat diet, no fasting for life

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Glucose-6-phosphatase deficiency

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Can't generate glucose from glycogen stores or via gluconeogenesis

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Glucose-6-phosphatase symptoms

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Hypoglycemia - no glucose from glycogen or gluconeogenesis
- Lactic acidemia - Gluconeogenesis, glycogen breakdown both make lactate
- Hyperuricemia - Pi locked up as G6P, not enough ATP in liver
- Increased ADP -> increased AMP -> increased IMP -> increased uric acid

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Pyruvate kinase deficiency pathogenesis

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Hemolytic anemia
- RBC's totally dependent on glycolysis
- no pyruvate kinase - no ATP
- No ATP - fragile cells that die early

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Pyruvate kinase body compensation

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Increased levels of DPG 2,3
- Reduces Hb affinity for O2, allows them to survive with fewer RBC's
- Still need transfusions, treatment

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Thiamine (B1) deficiency (Wernicke-Korsakoff, Beriberi)

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Typically alcoholics who take in empty calories
- Problems with PDH

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Glucose administration to alcoholics

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Give them thiamine with/before glucose
- Thimine deficiency means PDH can't work
- Lactate build-up, lactic acidotic brain damage ensues...

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Homocystenuria

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Build-up of homocysteine
- This pathway is only route for body to get rid of methionine

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Homocystenuria Pathogenesis

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Usually Methionine --> Homocysteine --> Cystathionine --> Cysteine
-Homocysteine --> Cystathionine via Cystathionine synthase, cofactor B6 (pyridoxal phosphate)
-Defect in one of various genes = synthase defects

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Homocystenuria Treatment

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1) High doses of B6 can force mutants to act normal
2) Low methionine diet
3) Betaine - converts homocyteine back to methionine

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Homocystenuria symptoms

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Mental retardation
- Vision problems
- Osteoporosis
- Arterial and venous thromboses