Biochem FA - p72 - 85 Metabolism Flashcards
What is fomepizole used for?
How does it do that?
antidote For Overdoses of Methanol or Ethylene glycol
blocks alcohol DH
What causes the hangover symptoms of disulfiram?
Acetaldehyde buildup
Disulfiram blocks acetaldehyde dehydrogenase–> ^ acetaldehyde –> ^ hangover symptoms –> discouraging drinking.
What is the limiting reagent in ethanol metabolism?
NAD+
How does alcohol DH in terms of pharmacokenetics?
zero-order kinetics
What does the ^ NADH/NAD+ ratio caused by ethanol metabolism lead to?
Lactic acidosis
Fasting hypoglycemia
Ketoacidosis
Hepatosteatosis
Ethanol metabolism ^ NADH/NAD+ ratio in liver causes lactic acidosis - how?
^ pyruvate conversion to lactate
Ethanol metabolism ^ NADH/NAD+ ratio in liver causes fasting hypoglycemia - how?
low gluconeogenesis due to ^ OAA –> malate
Ethanol metabolism ^ NADH/NAD+ ratio in liver causes ketoacidosis - how?
via diversion of acetyl-CoA into ketogenesis rather than TCA cycle
Ethanol metabolism ^ NADH/NAD+ ratio in liver causes hepatosteatosis - how?
^ conversion of DHAP –> glycerol-3-P; acetyl-CoA diverges into fatty acid synthesis, which combines with glycerol-3-P to synthesize triglycerides
^ NADH/NAD+ ratio disfavors ___ _____ Where does the ^ acetyl-CoA go?
TCA cycle
^ acetyl-CoA used in ketogenesis (–>ketoacidosis), lipogenesis (–> hepatosteatosis)
Sites of metabolism
Mitochondria, cytoplasm
What metabolic processes occur in the mitochondria?
Fatty acid oxidation (β-oxidation)
acetyl-CoA production
TCA cycle
oxidative phosphorylation
ketogenesis
What metabolic processes occur in the cytoplasm?
Glycolysis
HMP shunt
synthesis of cholesterol (SER), proteins (ribosomes, RER), fatty acids, and nucleotides.
What metabolic processes occur in both the mitochondria and the cytoplasm?
Heme synthesis, Urea cycle, Gluconeogenesis
HUGs take two (both)
MC metabolism = UGH (get it mcdonalds ahahaha)
function of kinase + ex
Catalyzes transfer of a phosphate group from a high-energy molecule (usually ATP) to a substrate (eg, phosphofructokinase).
fxn of phosphorylase + ex
adds inorganic phosphate onto substrate without using ATP (eg, glycogen phosphorylase)
fxn of phosphatase + ex
Removes phosphate group from substrate (eg, fructose-1,6-bisphosphatase)
fxn of Dehydrogenase + ex
Catalyzes oxidation-reduction reactions (eg, pyruvate dehydrogenase).
fxn of Hydroxylase + ex
Adds hydroxyl group (−OH) onto substrate (eg, tyrosine hydroxylase).
fxn of Carboxylase + ex
Transfers CO2 groups with the help of biotin (eg, pyruvate carboxylase).
fxn of Mutase + ex
Relocates a functional group within a molecule (eg, vitamin B12–dependent methylmalonyl-CoA mutase
fxn of Synthase/synthetase + ex
Joins two molecules together using a source of energy (eg, ATP, acetyl-CoA, nucleotide sugar)
rate limiting enzyme of Glycolysis
Phosphofructokinase-1 (PFK-1)
regulators of glycolysis
AMP (+), F-2,6-BisP (+)
ATP (-), citrate (-)
rate limiting enzyme of gluconeogenesis
Fuctose-1,6-bisphosphatase
regulators of gluconeogenesis
citrate (+)
AMP (-), F-2,6-BisP (-)
rate limiting enzyme of TCA cycle
Isocitrate DH
regulators of TCA cycle
ADP (+)
ATP (-), NADH (-)
rate limiting enzyme of Glycogenesis
glycogen synthase
regulators of Glycogenesis
G-6-P (+), insulin (+), cortisol (+)
epi (-), glucagon (-)
rate limiting enzyme of glycogenolysis
glycogen phosphorylase
regulators of glycogenolysis
epi (+), glucagon (+), AMP (+)
G-6-P (-), insulin (-), ATP (-)
rate limiting enzyme of de novo pyrimidine synthesis
carbamoyl phosphate synthetase II
regulators of de novo pyrimidine synthesis
ATP (+), PRPP (+)
UTP (-)
rate limiting enzyme of de novo purine synthesis
glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
regulators of de novo purine synthesis
AMP (-), inosine monophosphate (IMP) (-), GMP (-)
rate limiting enzyme of HMP shunt
Glucose-6-phosphate dehydrogenase (G6PD)
regulators of HMP shunt
NADP+ (+)
NADPH (-)
rate limiting enzyme of urea cycle
carbamoyl phosphate synthetase I
regulators of urea cycle
N-acetylglutamate (+)
rate limiting enzyme of Fatty acid synthesis
Acetyl-CoA carboxylase (ACC)
regulators of Fatty acid synthesis
insulin (+), citrate (+)
glucagon (-), palmitoyl-CoA (-)
rate limiting enzyme of Fatty acid oxidation
Carnitine acyltransferase I
regulators of Fatty acid oxidation
Malonyl-CoA (-)
rate limiting enzyme of Ketogenesis
HMG-CoA synthase
regulators of Ketogenesis
there are none listed haha tricked you have a wonderful day (^:
rate limiting enzyme of cholesterol synthesis
HMG-CoA reductase
regulators of cholesterol synthesis
insulin (+), thyroxine (+), estrogen (+) glucagon (-), cholesterol (-)
+ deficiency of (4) name?
Sx?
von Gierke disease (GSD I)
Severe fasting hypoglycemia,
^^ Glycogen in liver and
kidneys, ^ blood lactate,
^ triglycerides, ^ uric acid
(Gout), and hepatomegaly,
renomegaly. Liver does not
regulate blood glucose.
Glucose-6-phosphatase deficiency
Universal e(-) acceptors
Nicotinamides (NAD+, NADP+ from Vitamin B3)
Flavin nucleotides (FAD from Vitamin B2)
NADPH is a product of
HMP shunt
NADPH is used in:
Anabolic processes (eg steroid and FA synthesis)
Respiratory burst
CYP-450 system
Glutathione reductase
Enzymes and cofactors of pyruvate dehydrogenase complex
- Thiamine pyrophosphate (B1)
- Lipoic acid
- CoA (B5, pantothenic acid)
- FAD (B2, riboflavin)
- NAD+ (B3, niacin)
Tender Loving Care For Nancy
PDH activated by:
^ NAD+/NADH ratio
^ADP
^Ca2+
What inhibits lipoic acid?
What clinical findings can be seen in its poisoning?
Arsenic inhibits lipoic acid. Arsenic poisoning clinical findings:
imagine a vampire (pigmentary skin changes, skin cancer), vomiting and having diarrhea, running away from a cutie (QT prolongation) with garlic breath.
PDH complex deficiency leads to…
a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
X-linked.
PDH complex deficiency findings
Neurologic defects, lactic acidosis, ^ serum alanine starting in infancy.
PDH complex deficiency treatment:
^ intake of ketogenic nutrients (eg, high fat content or ^ lysine and leucine).
Different pathways of pyruvate metabolism
(enzymes and cycle name)
<–ALT–> Alanine (Cahill cycle)
Alanine AminoTransferase
–PC–> OAA (TCA)
Pyruvate carboxylase
–PDH–> Acetyl CoA (TCA)
<–LDH–> Lactate (cori cycle)
holy fuckkkkkkk TCA
pilanat?
ETC and oxid’v phosphorylation
NADH e-‘s from _______ enter _______ via malate-aspartate or _____________________ shuttle
NADH electrons from glycolysis enter mitochondria via the malate-aspartate or glycerol-3-phosphate shuttle.
_____ electrons are transferred to _______ __ (at a lower energy level than NADH). The passage of electrons results in the formation of a ______ ________ that, coupled to oxidative phosphorylation, drives the production of ___.
FADH2 electrons are transferred to complex II (at a lower energy level than NADH). The passage of electrons results in the formation of a proton gradient that, coupled to oxidative phosphorylation, drives the production of ATP.
Oxidative phosphorylation poisons:
Electron transport inhibitors
ATP synthase inhibitors
Uncoupling agents
how do electron transport inhibitors function?
Directly inhibit electron transport, causing a
dec proton gradient and block of ATP synthesis.
ex of Electron transport inhibitors + loc of fxn
Rotenone: complex one inhibitor.
“An-3-mycin” (antimycin) A: complex 3 inhibitor.
Cyanide, carbon monoxide, azide (the -ides,
4 letters) inhibit complex IV.
how do ATP synthase inhibitors fxn?
Directly inhibit mitochondrial ATP synthase, causing an ^ proton gradient. No ATP is produced because electron transport stops.
ATP synthase inhibitor ex
Oligomycin
how do uncoupling agents fxn?
^ permeability of membrane, causing a dec proton
gradient and ^ O2 consumption. ATP synthesis
stops, but electron transport continues.
Produces heat.
ex of uncoupling agents
2,4-Dinitrophenol (used illicitly for weight loss),
aspirin (fevers often occur after overdose),
thermogenin in brown fat (has more
mitochondria than white fat).
gluconeogenesis:
Occurs primarily in _____; serves to maintain euglycemia during _______. Enzymes also found in ______, _________ _______. Deficiency of the key gluconeogenic enzymes causes ___________.
(______cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase).
gluconeogenesis:
Occurs primarily in liver; serves to maintain euglycemia during fasting. Enzymes also found in
kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes causes hypoglycemia.
(Muscle cannot participate in gluconeogenesis because it lacks glucose-6-phosphatase).
odd vs even chain FAs
Odd-chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle (as succinyl-CoA), undergo gluconeogenesis, and serve as a glucose source.
Even-chain fatty acids cannot produce new glucose, since they yield only acetyl-CoA equivalents.
oxidizing agents that can lead to hemolytic anemia due to poor RBC defense against them
fava beans,
sulfonamides, nitrofurantoin, primaquine/
chloroquine, antituberculosis drugs).
Essential fructosuria defect
fructokinase
Essential fructosuria sx
fructose appears in blood and urine
Hereditary fructose
intolerance deficiency
aldolase B
Hereditary fructose
intolerance leads to..?
Fructose-1-phosphate accumulates,
causing a dec in available phosphate, which results in inhibition of glycogenolysis and
gluconeogenesis.
hereditary fructose intolerance Sx
hypoglycemia, jaundice, cirrhosis, vomiting
Symptoms present following consumption of fruit, juice, or honey
Hereditary fructose
intolerance Dx
Urine dipstick will be ⊝ (tests for glucose only); reducing sugar can be detected in the urine (nonspecific test for inborn errors of carbohydrate metabolism).
Galactokinase deficiency defect, and leads to..?
galactokinase.
Galactitol accumulates if galactose is present in diet.
Galactokinase
deficiency Sx
galactose appears in blood (galactosemia) and urine (galactosuria); infantile cataracts.
May present as failure to track objects or to develop a social smile. Galactokinase deficiency is
kinder (benign condition).
Classic galactosemia, deficiency of?
galactose-1-phosphate uridyltransferase.
Classic galactosemia damage caused by..?
Damage is caused by
accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).
classical galactosemia Sx
Symptoms develop when infant begins feeding (lactose present in breast milk and routine formula)
and include failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can
predispose to E coli sepsis in neonates.
classical galactosemia Tx
Treatment: exclude galactose and lactose (galactose + glucose) from diet.
_____ —> Sorbitol —> ____
enz.s involved?
glucose —> Sorbitol —> fructose
enz.s involved: aldose reductase, sorbitol dh
risk of intracellular sorbitol accumulation
osmotic damage (eg cataracts, retinopathy, and peripheral neuropathy seen with chronic hyperglycemia in diabetes).
locations with both aldose reductase and sorbitol dehydrogenase
Liver, Ovaries, and Seminal vesicles have both enzymes (they LOSe sorbitol).
locations with primarily/only aldose reductase
Lens has primarily aldose reductase. Retina, Kidneys, and Schwann cells have only aldose
reductase (LuRKS).
Lactase function location + function
Lactase functions on the intestinal brush
border to digest lactose (in milk and milk products) into glucose and galactose.
Causes of lactase deficiency
Primary: age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American descent.
Secondary: loss of intestinal brush border due to gastroenteritis (eg, rotavirus), autoimmune disease.
Congenital lactase deficiency: rare, due to defective gene.
lactase defncy Dx
Stool demonstrates dec pH and breath shows INC hydrogen content with lactose hydrogen breath test.
Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
lactase defncy Sx
bloating, cramps, flatulence, osmotic diarrhea
lactase defncy Tx
Avoid dairy products or add lactase pills to diet; lactose-free milk
essential Amino Acids
PVT TIM HaLL: Phenylalanine, Valine, Tryptophan, Threonine, Isoleucine, Methionine, Histidine, Leucine, Lysine.
glucogenic amino acids
Methionine, histidine, valine. I met his valentine, she is so sweet (glucogenic).
ketogenic amino acids
leucine, lysine.
The onLy pureLy ketogenic amino acids
glucogenic/ketogenic amino acids
Isoleucine, phenylalanine, threonine, tryptophan.
Acidic amino Acids
Aspartic acid, glutamic acid.
Negatively charged at body pH.
Basic amino acids
Arginine, histidine, lysine.
Arginine is most basic. Histidine has no charge at body pH.
Arginine and histidine are required during periods of growth.
Arginine and lysine are in histones which bind negatively charged DNA.
His lys (lies) are basic.
WHAT THE FUCK IS THE UREA CYCLE
IT IS HOW WE REMOVE EXCESS NITROGEN HELL YES GO TEAM HOMO SAPIENS
hyperammonemia, causes of?
Can be acquired (eg, liver disease) or hereditary
(eg, urea cycle enzyme deficiencies).
hyperammonemia Sx
Presents with flapping tremor (eg, asterixis),
slurring of speech, somnolence, vomiting,
cerebral edema, blurring of vision.
hyperammonemia leads to..
^ NH3 depletes glutamate in the CNS, inhibits TCA cycle (low α-ketoglutarate).
hyperammonemia Tx
Treatment: limit protein in diet.
May be given to dec ammonia levels:
– Lactulose to acidify GI tract and trap NH4+ for excretion.
– Antibiotics (eg, rifaximin, neomycin) to dec ammoniagenic bacteria.
– Benzoate, phenylacetate, or phenylbutyrate
react with glycine or glutamine, forming
products that are excreted renally.
Ornithine
transcarbamylase
deficiency does what
Interferes with the body’s ability to eliminate ammonia.
Excess carbamoyl phosphate is converted
to orotic acid (part of the pyrimidine synthesis pathway).
Ornithine
transcarbamylase
deficiency findings
Findings: ^ orotic acid in blood and urine, Inc BUN, symptoms of hyperammonemia. No megaloblastic anemia (vs orotic aciduria).
Causes of Phenylketonuria
Due to dec phenylalanine hydroxylase or
dec tetrahydrobiopterin (BH4) cofactor
(malignant PKU). Tyrosine becomes essential.
^ phenylalanine –> ^ phenyl ketones in urine.
PKU findings
intellectual disability, growth
retardation, seizures, fair complexion, eczema,
musty body odor.
Disorder of aromatic amino acid metabolism
-> musty body odor.
PKU Tx
low phenylalanine and ^ tyrosine in
diet, tetrahydrobiopterin supplementation.
PKU patients must avoid the artificial sweetener
aspartame, which contains phenylalanine.
Maternal PKU
cause and findings in infant
lack of proper dietary therapy during pregnancy.
Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
Maple syrup urine disease
cause of and leads to..?
Blocked degradation of branched amino
acids (Isoleucine, Leucine, Valine) due to
low branched-chain α-ketoacid dehydrogenase
(B1). Causes ^ α-ketoacids in the blood,
especially those of leucine.
MSUD Sx
Presentation: vomiting, poor feeding, urine
smells like maple syrup/burnt sugar. Causes
severe CNS defects, intellectual disability,
death.
MSUD Tx
restriction of isoleucine, leucine, valine in diet, and thiamine supplementation.
Alkaptonuria defncy
Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate
-> pigment-forming homogentisic acid builds up in tissue
Alkaptonuria findings
Findings: bluish-black connective tissue, ear cartilage, and sclerae (ochronosis); urine turns black on prolonged exposure to air.
May have debilitating arthralgias (homogentisic acid toxic to cartilage).
causes of homocystinuria
- Cystathionine synthase deficiency
- low affinity of cystathionine synthase for pyridoxal phosphate
- Methionine synthase (homocysteine methyltransferase) deficiency
- Methylenetetrahydrofolate reductase (MTHFR) deficiency
Homocystinuria Sx
HOMOCYstinuria: ^^ Homocysteine in urine, Osteoporosis, Marfanoid habitus, Ocular changes (downward and inward
lens subluxation), Cardiovascular effects (thrombosis and atherosclerosis -> stroke and MI), kYphosis, intellectual disability, fair complexion. In homocystinuria, lens subluxes “down and in” (vs Marfan, “up and fans out”).
Cystathionine synthase deficiency
treatment
low methionine, ^ cysteine, ^ B6, B12, and folate in diet
low affinity of cystathionine synthase for
pyridoxal phosphate treatment
^^ B6 and ^ cysteine in diet
Methionine synthase (homocysteine methyltransferase) deficiency treatment
^ methionine in diet
Methylenetetrahydrofolate reductase (MTHFR) deficiency treatment
^ folate in diet
Cystinuria is a heriditary defect of ___ and ______ that prevents reabsorption of ____, ____, ____, and ____.
Cystinuria is a hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystine, Ornithine, Lysine, and Arginine (COLA).
Excess cystine in the urine can lead torecurrent
precipitation of _____ _____ _____
Excess cystine in the urine can lead to recurrent
precipitation of hexagonal cystine stones
Cystinuria treatment
Treatment: urinary alkalinization (eg, potassium citrate, acetazolamide) and chelating agents (eg, penicillamine) ^ solubility of cystine stones; good hydration.
Propionic acidemia is a deficiency of..?
Autosomal recessive deficiency of propionyl-
CoA carboxylase -> ^ propionyl-CoA, low methylmalonic acid.
Propionic acidemia Sx
poor feeding, vomiting, hypotonia,
anion gap metabolic acidosis, hepatomegaly,
seizures.
Propionic acidemia Tx
low protein diet that does not
include isoleucine, methionine, threonine,
valine
Substances that metabolize into propionyl-CoA
Substances that metabolize into propionyl-CoA
cause you to VOMIT:
Valine
Odd-chain fatty acids
Methionine
Isoleucine
Threonine.
