Biochemistry: Metabolism Flashcards
Why is fomepizole used as antidote for ODing on methanol or ethylene glycol?
Blocks alcohol dehydrogenase enzyme from converting ethanol -> acetaldehyde
- doesnt show symptoms if in ethanol stage and is easily excreted
General ethical metabolism cycle
Ethanol -> acetaldehyde -> acetate
1) ethanol -> acetaldehyde requires alcohol dehydrogenase enzyme activity
- catalase, NAD+ and CYP2E1 are cofactors in this step, generating water, NADH and ROS in the process
- occurs in cytosol
2) acetaldehyde-> acetate requires acetaldehyde dehydrogenase enzyme activity
- NAD+ is a cofactor in this step, generating NADH in th eprocesds
- occurs in mitochondria
- acetaldehyde is the product that actually induces alcoholic symptoms*
- works under zero-order kinetics*
- NAD+ is rate limiting*
Why is Disulfiram used to discourage alcohol consumption in alcoholics?
It blocks acetaldehyde dehydrogenase activity, which leads to a build up of acetaldehyde.
Acetaldehyde produces hangover/alcoholic symptoms in mass, so it becomes uncomfortable to patients.
What are the 4 main consequences of ethanol metabolism in the body?
- ALL due to increased NADH/NAD+ ratio (less NAD+)*
1) lactic acidosis
- increased pyruvate production since TCA is limited
2) fasting hypoglycemia
- decreased gluconeogenesis due to increased malate from OAA production.
3) keto acidosis
- increased ketogenesis and decreased TCA cycle acetyl-CoA usage
4) hepato-steatosis
- increased production of glycerol-3-P
What metabolism is done in mitochondria
FA-oxidation (beta-oxidation)
Acetyl-CoA production
TCA cycle
Oxidative phosphorylation
Ketogenesis
What metabolism is done in the Cytoplasm
Glycolysis
HMP shunt
Cholesterol synthesis and metabolism
protein production
What metabolism is conducted in both the mitochondria AND the cytosol?
Heme synthesis
Urea cycle
Gluconeogenesis
“Takes two to HUG”
What is the function of a kinase
Transfers a phosphate group from ATP or NADHP to a substrate
What is the function of a phosphorylase?
Adds inorganic phosphate onto a substrate without the use of ATP/NADPH
What is the function of a Dehydrogenase
Catalzyes oxidation:reduction reactions
- takes adds or removes hydrogen ions
What is the function of a Hydroxylase
Adds hydroxyl (OH) groups to a substrate
What is the function of a carboxylase?
Transfers (CO2) groups from a substrate to another
- uses cofactor biotin
What is the function of a mutase?
Relocates a functional group on a substrate (but does not remove or transfer it)
What is the function of a synthase/synthetase?
Bonds two molecules together using ATP, acetyl CoA or sugar
What is the rate determining enzyme and regulator molecules for glycolysis?
Rate determine enzyme: PFK-1
positive regulators:
- AMP
- fructose 2,6 BP
Negative regulators:
- ATP
- citrate
(negative feedback mechanism)
What is the rate determining enzyme and regulator molecules for gluconeogenesis?
Rate determining enzyme:
- Fructose 1,6 BP
Negative regulators
- AMP
- fructose 2,6 BP
(Is turned off in the presence of glycolysis, and turned on when glycolysis is turned off)
What is the rate determining enzyme and regulator molecules for TCA cycle?
Rate determining enzyme:
- isocitrate dehydrogenase
Positive regulators:
- ADP
Negative regulators
- ATP
- NADH
(Negative feedback mechanism)
What is the rate determining enzyme and regulator molecules for glycogenesis?
Rate determining enzyme:
-glycogen synthase
Positive regulators:
- glucose-6P
- insulin
- cortisol
Negative regulators:
- epinephrine
- glucagon
(only turned off when you need glucose or are diabetic without insulin)
What is the rate determining enzyme and regulator molecules for Glycogenolysis?
Rate determining enzyme:
- glycogen phosphorylase
Positive regulators
- epinephrine
- glucagon
- AMP
Negative regulators:
- glucose 6P
- insulin
- ATP
(Turned off when resting)
What is the rate determining enzyme and regulator molecules for HMP shunt?
Rate determining enzyme:
- glucose 6P dehydrogenase (G6PD)
Positive regulators
- NADP
Negative regulators
- NADPH
(Turned on when you need excess energy and kinase activity)
What is the rate determining enzyme and regulator molecules for ketogenesis?
Rate determining enzyme:
- HMG-CoA synthase
What is the rate determining enzyme and regulator molecules for cholesterol synthesis?
Rate limiting enzyme:
- HMG-CoA reductase
Positive regulators:
- insulin
- thyroxine
- estrogen
Negative regulators:
- glucagon
- cholesterol
Pyruvate dehydrogenase deficiency
X-linked recessive disorder that causes a mutation in the E1-alpha gene.
- Results in low/null pyruvate dehydrogenase activity and decreased production of acetyl-CoA
- causes TCA cycle impairment and pyruvate accumulation
Pyruvate accumulation leads to increased anaerobic respiration and transformation of pyruvate to lactate and alanine
- results in lactic acidosis
Can be severe ( presents at birth with congenital brain malformations) or moderate (presents in infancy and childhood)
Symptoms/signs:
- microcephaly
- blindness
- mental retardation
- Leigh syndrome (gray matter degeneration with capillary proliferation)
- *Cheyne-stokes breathing patterns and dyspnea (results from lactic acidosis)
- hypotonia
- ataxia
- progressive encephalopathy
- abnormal eye movements
- increased lactate, pyruvate and alanine levels in serum/urine
- MRI shows cerebral atrophy, corpus callosum absence and medullary pyramid absence
Treatment:
- thiamine, carnitine and lipoid acid supplementation
- keto diet
- dicholoracetate (synthetic Pyruvate dehydrogenase)
What muscle biopsy sign is common in most mtDNA disorders?
Ragged-red fibers throughout the myocytes
