BIOCHEMISTRY: DISEASES / DISORDERS  -Ketoglutarate impairs the function of TCA cycle in neurons

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GENETIC DISORDERS -
Symptoms:
¤ HYDROXYPROLINE & HYDROXYLYSINE ¢ Tremor
- Occur in collagen ¢ Slurred Speech
- No tRNA for these hydroxylated A.A, dietary forms are not incorporated ¢ Blurred Vision
during CHON synthesis ¢ Coma
- Requirements: -Ketoglutarate, Fe2+, Ascorbate and O2 ¢ Death
- Catalyzed by: Mixed-function oxidases which requires Vitamin C ¤ GLUTAMINE SYNTHASE
- Vitamin C deficiency would lead to SCURVY, which would fail to provide - Catalyze the reaction of Glutamate to Glutamine
substrates for cross-linking of maturing collagen

¤ SELENOPROTEINS
- 25 are known in human
- Ex: Selenocysteine, which may be present in enzymes that catalyze
- NH3 detoxification
Redox reactions, replacement of selenocysteine with cysteine can
- Rare Deficiency in NEONATES  severe brain damage, multi-organ
impair catalyte activity
failure and death
- Impairments have been implicated in TUMORIGENESIS,
ATHEROSCLEROSIS and associated with SELENIUM DEFICIENCY
DIABETES MILLETUS
CARDIOMYOPATHY (KESHAN DISEASE)
¤ TYPE I
- Impaired synthesis or secretion of insulin
AMMONIA (NH3) INTOXICATION
- Juvenile onset, Insulin Dependent
- NH3 is rapidly removed by the liver, normal value in blood: 10-20g/dl
¢ POORLY CONTROLLED DM
- Excess, toxic to CNS
- Patient becomes HYPERGLYCEMIC
- In the brain, it reacts with -Ketoglutarate to form glutamate
 - Due to lack of insulin to stimulate uptake & utilization of glucose
- Absence of insulin to antagonize actions of glucagon
- lipolysis in adipose tissue which results in NEFA (substrates for
ketogenesis in liver)
Glycation – NON-ENZYMATIC attachment of sugars
-  blood glucose =  glycation of CHONs
- alters properties in Extracellular Matrix
Glycated Hemoglobin (HbA1C)
- Blood glucose enters RBCs, it glycates the -amino group of lysyl residues
& amino terminals of Hgb
- HbA1C (5%) is proportionate to blood glucose conc. which is  in patients
with uncontrolled DM because of consistent  of blood glucose conc.
¤ TYPE II
- Impaired sensitivity of tissues to insulin action
- Adult-onset, Non-insulin dependent
Insulin – acts to lower blood glucose immediately by enhancing glucose transport
into adipose tissue
Drugs: Sulfonylurea, Tolbutamide, Glyburide are used to stimulate insulin
secretion via ATP-sensitive K+ channels
Ketosis – occurs in starvation & involves depletion of available carbohydrates
coupled with mobilization of FFA, which is severe in DM
LACTOSE INTOLERANCE
- Result of lactase deficiency, lactase are enzymes found in the brush
border of the intestinal mucosal cells
- Lactose remains in the intestinal lumen which will become a substrate for
bacterial fermentation to lactate which leads to abdominal discomfort
- Symptoms: Diarrhea and instestinal discomfort when lactose is consumed
DISACCHARIDASES DEFICIENCY
1. Lactase Deficiency – Lactose Intolerance
2. Sucrase Deficiency – Sucrose Intolerance
FATTY LIVER
¤ NON-ALCHOHOLIC FATTY LIVER DISEASE (NAFLD)
- Most common liver disorder
- Accumulation of lipids in the liver
2 Categories:
1. Raised levels of plasma FFA
- Production of VLDL doesn’t keep pace with the  influx &
esterification of FFA, allowing TAG to accumulate
- Occurs in starvation, feeding of high-fat diets
2. Metabolic block in the production of plasma lipoCHONs
- TAG accumulates due to:
a. Block in apolipoCHON synthesis
b. Block in lipoCHON synthesis from lipids & apolipoCHON
c. Failure of provision of phospholipids
d. Failure of the secretory mechanism itself
¤ ALCHOLIC FATTY LIVER
- Caused by alcoholism which leads to cirrhosis
- Combination of impaired F.A oxidation &  lipogenesis
- Oxidation of ethanol by alcohol dehydrogenase leads to excess
production of NADH, which competes with reducing equivalents from
other substrates, including F.A from respiratory chain
- Inhibited oxidation causes  esterification of F.A to form TAG  Fatty
Liver
ALCOHOLISM
- Gluconeogenesis is dependent upon F.A oxidation, any impairment of F.A
oxidation leads to HYPOGLYCEMIA
- There is inhibition of F.A oxidation which causes the hypoglycaemia in
alcoholism
ATHEROSCLEROSIS - Patients would have xanthinuria & xanthine lithiasis
- Deposition of cholesterol and cholesterol esters in the artery walls  esp.
from oxidized LDL DIHYDROTESTOSTERONE
- Oxidized LDLs can cause endothelial lining damage which predisposes to - Most significant metabolic product of testosterone
atherosclerosis - Active form of the hormone in many tissues
- Normal value: 400g/day
HYPERCHOLESTEROLEMIA
- LDL receptor is defective in familial hypercholesterolemia
- Genetic condition wherein there is  LDL cholesterol

MULTIPLE SCLEROSIS
- Demyelinating disease
- Loss of both phospholipids (ethanolamine plasmalogen) & sphingolipids
from white matter
- CSF: phospholipid levels

GOUT
- Metabolic disorder of purine catabolism
- Genetic defect in PRPP synthase (Reaction 1)
- Results in overproduction / overexcretion of purine catabolists
- Sodium urate crystallizes in soft tissues & joints  inflammatory reaction
- Most causes reflect abnormalities in renal handling of uric acid

ALCOHOL & GOUT

- Oxidation of ethanol leads to formation of aldehyde by aldehyde
dehydrogenase, producing acetate
- NADH/NAD ratio causes lactate/pyruvate  hyperlacticacidemia,
decreases excretion of uric acid aggravating gout

HYPERURICEMIA
- excretion of hypoxanthine & xanthine
-  xanthine oxidase due to genetic defect or severe liver disease