Metabolism Random Flashcards
Disulfiram
inhibits ALDH (acetaldehyde dehydrogenase): this will cause buildup of acetaldehyde which causes the Sx of EtOH hangovers
used to discourage drinking
Fomepizole
inhibits ADH (alcohol dehydrogenase)
used as antidote For Overdoses of Methanol or Ethylene glycol
Ethanol metabolism pathway
Ethanol -> acetaldehyde (ADH) in cytosol -> acetate (ALDH) in mitochondria
Uses up a lot of NAD+ so you end up with a lot of NADH around
CYP2E1
used as overflow pathway when the regular ethanol metabolism system is overloaded in the MICROSOME
this enzyme also metabolizes a lot of other drugs (ex. Tylenol)
Consequences of ethanol metabolism
- increased NADH/NAD+ ratio
- energy depletion: TCA cycle is blocked, increased lactic acidosis
- Hypoglycemia: gluconeo. and glycolysis are blocked
- increased acetyl coA: FA synthesis accelerated, ketoacidosis
Rate limiting enzyme in glycolysis
PFK-1
Hexokinase vs. Glucokinase: location, Km, Vmax
Glucokinase: located in liver and beta cells of pancreas, has HIGH Km aka LOW affinity, has a HIGH Vmax aka works quickly
Hexokinase: located in most tissues except liver and beta cells of pancreas, has LOW Km aka HIGH affinity, has a LOW Vmax aka slower
End products of glycolysis
2 Pyruvate, 2 NADH, 2 ATP (4 total but 2 consumed)
Rate limiting enzyme for gluconeogenesis
Fructose 1,6 bisphosphatase
Pyruvate dehydrogenase complex function and cofactors
Links glycolysis and the TCA cycle
Requires TLC for Nancy: Thiamine (B1) Lipoic acid CoA (B5) FAD (B2) NAD (B3)
Is activated when it is dephosphorylated by PDH phosphatase (ie during exercise)
Pyruvate dehydrogenase deficiency
Buildup of pyruvate that is shunted to lactate (via LDH) and alanine (via ALT)
X linked disorder
Lactic acidosis
Increase in serum alanine starting in infancy
Tx: increase ketogenic nutrients (fat, lysine, leucine)
HMP shunt purpose
provides a source of NADPH from glucose-6P
NADPH is required for glutathione reduction inside RBCs, fatty acid and cholesterol biosynth
Provides source of ribose (nucleotide synthesis; glycolytic intermediates
No ATP used OR produced
HMP reactions (oxidative and nonoxidative)
Oxidative is irreversible, uses G6PD, and produces NADPH
Non oxidative is reversible, uses transkelotases and phosphopentose isomerase, requires B1, and produces G3P and ribose
G6PD deficiency
X linked recessive
NADPH needed for glutathione reduction
Glutathione detoxifies free radicals in RBCs
Hemolytic anemia bc of poor RBC defense against oxidizing agents
Oxidizing agents: fava beans, sulfonamides, primaquine, antiTB drugs
Infection can ppt hemolysis bc inflamm response produces free radicals–>oxidative damage
Peripheral smear: heinz bodies (denatured Hb ppts within RBC), bite cells (phagocytic removal of heinz bodies by splenic macrophages)
Fructose metabolism pathway
Fructose–(fructokinase–>fructose 1 P–(adolase B)–>…met continues…
Essential fructosuria
Autosomal recessive
Defect in fructokinase
Benign, asymptomatic bc fructose is not trapped in cells
Fructose in blood and urine
Fructose intolerance
Autosomal recessive
Deficiency in adolase B
Fructose 1 P accumulates–>decrease in available phosphate–>inhibition of glycolysis and gluconeogenesis
Symptoms after consumption of fruit, juice, honey
Negative urine dipstick (tests for glucose only)
Reducing sugar can be detected in urine
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting
Tx: decrease fructose and sucrose intake
Galactose metabolism pathway
Galactose can either go:
Galactose–(galactokinase)–>galactose 1 P–(uridyltransferase)–>glucose 1 P–>glycolysis
OR
galactose –(aldose reductase)–>galactitol
Galactokinase deficiency
Galacitol accumulates if galactose is present in diet
Mild
Symptoms begin when infant breast/formula feeds
Galactosemia, galactosuria, infantile cataracts
Infant may have failure to track objects or to develop a social smile
Classic galactosemia
Severe
Absence of galactose-1-phosphate uridyltransferase
Aut recess
Damage due to accumulation of galacitol, which accum in the lens of the eye, and P depletion
Failure to thrive, jaundice, hepatomeg, cataracts, intellect disability
Can –> e coli sepsis in neonates
Tx: exclude galactose and lactose from diet
FAB GUT pneumonic:
fructose adolase B, galactose to uridyltransferase
Sorbitol
Alcohol counterpart of glucose
glucose–(aldose reductase)–>sorbitol–(sorbitol dehydrogenase)–>fructose
Traps glucose in the cell; tissues that do not have sorbitol dehydrogenase get intracell sorbitol accumulation
Schwann cells, retina, kidney, and lens (mostly) only have aldose reductase
–>cataracts, retinopathy, peripheral neuropathy
problem in chronic hyperglycemia DM pts
Lactase function and deficiency
–>dietary lactose intolerance
lactase functions on brush border to digest lactose–>glucose + galactose
Primary due to age dependent decline after childhood
Secondary due to losh of brush border (gastrienteritis from rotavirus, autoimmune)
Congenital deficiency is rare
Findings: bloating, cramps, flatulence, osmotic diarrhea
Urea cycle function and important players
Nitrogen excretion; occurs in liver
Part in mitochondria, part in cytoplasm
Carbamoyl phosphate synthetase I is RLS; it requires N-acetylglutamate as an allosteric activator
Ornithine transcarbamylase converts ornithine–>citruline
Disorders–>hyperammonemia (confusion, vomiting, tachypnea)
Cahill and Cori cycle
Transport ammonia between muscle and liver; uses alanine and glutamate
Uses alphaketoglutarate
Hyperammonemia
Acquired (liver disease) or inherted
Excess NH3–>depletes alphaketoglutarate–>inhibition of TCA cycle
Tx with limited protein diet
Tremor, slurring of speech, vomiting, cerebral edema, blurred vision
Meds that lower ammonia levels:
lactulose (acidifies GI tract–>NH4 excreted)
Rifaximin (decreases ammoniagenic bacteria)
Benzoate, phenylacetate, phenylbutyrate (binds to NH4–>excretion)
N-acetylglutamate synthase deficiency
Autosomal recessive
Required cofactor for CPS1
Hyperammonemia
Neonates: poorly regulated resp and body temp, poor feeding, developmental delay, intellect disability (same as CPS1 deficiency)
Ornithine transcarbamylase deficiency
X linked recessive
most common urea cycle disorder
excess carbamoyl phosphate is converted to orotic acid (part of pyrimidine synthesis pathway)
Findings: increased orotic acid in blood and urine, low BUN, hyperammonemia,
No megaloblastic anemia (vs orotic aciduria, which is when there is low pyrimidine synthesis bc of megaloblastic anemia–>orotic acid accumulation)
Phenylketonuria - what’s the etiology?
deficient phenylalanine hydroxylase or BH4 cofactor
Phenylketonuria - what is the treatment?
Avoid phenylalanine (found in aspartame) and supplement tyrosine (becomes essential) and/or BH4 supplementation (depends on etiology)
Phenylketonuria - symptoms/presentation
Musty Crusty: musty body odor, eczema
intellectual disability, growth delay, seizures
fair skin & eczema
musty body odor (specifically sweat and urine)
albinism (tyrosine needed to make melanin)
excretion of phenylketones in urine (causes smell)
Babies are all screened on day 2/3 of life
What can happen to a pregnant woman with PKU?
If she is not keeping her PKU under control (following diet), the excess phenylalanine is teratogenic specifically to CNS development –> microcephaly, intellectual disability, growth retardation, congenital heart defects
Phenylketonuria - inheritance
Autosomal recessive (enzyme deficiency)
Maple syrup urine disease - etiology/pathogenesis
Deficient branched chain alpha ketoacid dehydrogenase (uses B1 as cofactor) - can’t degrade branched AA (Iso, Leu, Val)
Maple syrup urine disease - inheritance
Autosomal recessive (enzyme deficiency)
Maple syrup urine disease - sx/presentation
Urine that smells like maple syrup (duh!), vomiting, poor feeding - present in days 4-7 of life
Eventually –> CNS defects, intellectual disability, death (*Leucine crosses BBB and is responsible for the CNS effects)
Maple syrup urine disease - treatment
Avoid branched AAs in diet (Iso, Leu, Val) and supplement thiamine
Alkaptonuria - etiology/pathogenesis
Deficiency of homogentisate oxidase (tyrosine –> fumarate)
Alkaptonuria - inheritance
autosomal recessive (enzyme deficiency)
Alkaptonuria - symptoms/presentation
Blue-black coloration of cartilage (called ochronosis): connective tissue, ears, sclerae (brown pigment)
Urine will turn black when left out for a bit
Debilitating arthralgias, ankylosis, arthritis (toxic to cartilage)
*All due to effects of homogentisate build-up
Cofactors of branched-chain alpha-ketoacid dehydrogenase
5: TPP, lipoic acid, CoA, NADH, FADH2
Homocystinuria - etiology
3 types:
cystathione synthase deficiency
decreased affinity of cys synthase for B6 cofactor
methionine synthase deficiency
*All 3 lead to homocysteine build-up.
Homocystinuria - inheritance
All 3 types are autosomal recessive (enzyme deficiencies).
What reactions do cystathione synthase and methionine synthase catalyze?
CS: homocysteine + Ser –> Cystathione (*requires B6)
MS: Homocysteine –> Methionine (*req B9 + B12)
Homocystinuria - treatment(s)
CS deficiency: Cys, B9, B6, B12 supplementation + reduced methionine consumption
CS decreased affinity for B6: Cys + B6 supplementation
MS deficiency: supplement Methionine
Homocystinuria - sx/presentation
Marfanoid habitus but with down and in lens dislocation (Marfan’s is up and out)
Intellectual disability
Cystinuria - etiology
Autosomal recessive deficiency of renal transporter (in PCT) for COLA: cysteine, ornithine, lysine, arginine
Cystinuria - diagnostic test
Positive sodium cyanice-nitroprusside test:
Cyanide converts cystine to cysteine, cysteine binds nitroprusside, turning the solution purple.
Cystinuria - sx/presentation
Typically presents as renal kidney stones in a child, possibly as staghorn calculi.
Stones are radiolucent on XR
Crystals are hexagonal
Cystinuria - treatment
To prevent kidney stones:
alkalinization of urine (acetazolamide) and hydration/low salt diet are 1st line
chelation (penicillamine) if necessary
Rate limiting enzyme glycogenesis
glycogen synthase
Rate limiting enzyme glycogenolysis
glycogen phosphorylase
Arsenic poisoning: how does it present? why is it important for metabolism?
Inhibits lipoic acid in pyruvate dehydrogenase complex
Presents as garlic breath with GI Sx (vomiting, rice water stools), QT prolongation
End products of TCA cycle
3 NADH, 1 FADH2, 2 CO2, 1 GTP per acetyl CoA mc
10 ATP per acetyl CoA
20 ATP per glucose mc
