Biochem Flashcards
what is methotrexate’s MOA
folic acid analog that competitively inhibits DHF reductase
this decreases DNA synthesis
what can methotrexate be used in
rapidly dividing cells:
cancers ectopic pregnancy medical abortion (+ misoprostol) Rheumatoid Arthritis (1st line) Psoriasis
what are the 2 reasons for homocystinuria
Homocysteine can’t go one of two ways:
can’t go to Methionine
via Methionine synthase and B12
can’t go to Cystathione/Cysteine
via Cystathione-B-Synthase (CBS) and B6
how do you treat methionine-synthase deficient homocystinuria
high methionine in diet
methionine is now essential
how do you treat CBS-deficient homocystinuria
many respond dramatically to Vitamin B6 to “force” CBS activity
also reduce intake of methionine, which is the other direction of the homocysteine pathway
how does a homocystinuria pt present
marfanoid habitus kyphosis ectopia lentis osteoporosis developmental delay thrombosis, atherosclerosis (early COD)
very high homocysteine
Go through Fabry disease
“fabric”
bathing trunk, mittens and socks
-angiokeratomas in bathing trunk distribution
-acroparthesias (burning hands/soles)
you have a “galaxy” of skin spots
-alpha-galactosidase A
when you get older, you have to cover up your kidneys and heart with more fabric
-late stage = progressive renal failure, CVD
“Men fabricate lies about their hunting skills”
-Fabry and Hunter = X-linked
go through Gaucher disease
HSM (similar to Neimann-Pick) (1 and 2 on the page)
“crumpled grocery bag with your macros: pans, Erlenmeyer flasks, liver, glucose, and iPhone 3G”
- lipid laden macrophages resembling crumpled tissue paper
- macrophages
- pancytopenia
- Erlenmeyer flask femur bone deformities
- liver = HSM
- glucose and 3G = glucocerebrosidase, glucocerebroside
go through Neimann-Pick disease
HSM (similar to Gaucher) (1 and 2 on the page)
cherry-red spot (2 and 3 on the page; has a hyphen)
“No man would pick his nose with his springer because the boogers would make him fat”
- sphingomyelinase, sphingomyelin
- fat = HSM
go through Tay-Sach disease
cherry-red spot (2 and 3 on the page; has a hyphen)
“Tay-Sach lacks hexosaminidase”
Taylor’s gang has a weird build-up of onion-skin-heads with GM2’s on the side”
- onion-skin lysosomes
- GM2 ganglioside
go through Krabbe disease
“Grab a galaxy of milky boobs, bro”
- galaxy/milky and bro = galacto-cerebrosidease, galacto-crebroside
- boobs = globoid cells
go through Metachromatic Leukodystrophy
“Look at this trophy”
-leukodystrophy
“April Fools Day”
-Arylsulfatase
“See bro, so fake”
-cerebroside sulfate
go through Hurler syndrome
“Hurley (from Lost) tried to be tough like the Hunters, but wasn’t smart, couldn’t see, too fat, and too ugly”
- developmental delay
- corneal clouding
- HSM
- gargoylism/course facial features
both Hurler and Hunter accumulate Heparan sulfate
go through Hunter syndrome
"'Hunters see clearly and aggressively aim for the X" "Men hunt" -no corneal clouding -Hurler + aggressive behavior -X-linked
both Hurler and Hunter accumulate Heparan sulfate
“Men fabricate lies about their Hunting skills”
-Fabry and Hunter are X-linked
what is methylmalonic acidemia
metabolic acidosis 2/2 defective methylmalonyl-CoA mutase.
This enzyme normally converts Methylmalonyl-CoA to Succcinyl CoA, to enter the TCA cycle.
A defect in this enzyme will present in the neonatal period with:
- high methylmalonyl CoA (build up)!!
- high Propionyl CoA (previous step build up)!!
- hyperammonemia
- ketotic hypoglycemia
- metabolic acidosis
- lethargy, hypotonia, vomiting, respiratory distress
what are the functions of the HMP shunt
pentose phosphate pathway:
provides NADPH, used in:
- glutathione reduction in RBCs
- Fatty acid and cholesterol biosynthesis
- nucleotide synthesis
what is the rate-limiting enzyme for the HMP shunt
G6PD
glucose-6-phosphate dehydrogenase
what does transketolase do
allows reversible transition between:
Fructose-6-Phosphate and Ribose-5-Phosphate
The fructose-6-Phosphate is a glycolysis intermediate, which could go on to enter the TCA cycle to give ATP
the Ribose-5-Phosphate could go on to make nucleic acids
what are pyruvate’s options
it’s coming from PEP in the glycolytic pathway, so it’s planning to go to Acetyl-CoA via Pyruvate Dehydrogenase
and then enter the TCA cycle and provide energy.
but if Acetyl CoA is high, that shunts Pyruvate to skip over to make Oxaloacetate via Pyruvate Carboxylase
from here, the oxaloacetate can go back up to PEP via PEP carboxykinase and re-enter gluconeogenesis to provide blood glucose.
This would happen when a pt’s blood sugar levels are low. Acetyl-CoA’s high level helps the body make this decision to make more glucose in the blood.
what does a G6PD deficiency present with
hemolytic anemia during times of oxidative stress
because you’re not producing the NADPH to keep reducing glutathione in RBCs to prevent RBC damage.
The oxidative stress precipitates the Hb out as Heinz bodies, which are then removed by the spleen, creating bite cells
what enzyme deficiency can present similarly to G6PD deficiency
glutathione reductase
glutathione recutase helps use the NADPH to reduce the oxidized-glutathione back to regular/reduced/ready-to-use glutathione
it has similar consequences of cells precipitating out their Hb in oxidative stress situations because it’s unable to utilize the NADPH to keep reducing glutathione
how does orotic aciduria present
Early failure to thrive, developmental delay (physical and mental)
high orotic acid levels
megaloblastic anemia!!!
(NO hyperammonemia!!!)
(!!! = vs OTC deficiency)
defect in UMP synthase to catalyze orotic acid–> UMP, so you have high orotic acid buildup
treat with URIDINE supplementation
“when UR DINING “orrotic-ly” UR a mega-blast”
how does OTC deficiency present
high orotic acid levels
Hyperammonemia!!!
(NO megaloblastic anemia!!!)
(!!! = vs orotic aciduria)
defect in OTC, which is supposed to combine carbamoyl phosphate + Ornithine –> citrulline in the Urea cycle
excess Carbamoyl phosphate –> orotic acid
via pyrimidine synthesis pathway
“HYPER-AMMY takes too many OTC drugs in her PYRAMID CAR, so she’s not-a-blast”
what do spliceosomes remove
introns containing GU at the 5’ splice site and AG at the 3’ splice site
splice site mutations may result in removal of exons and retention of introns
when are ketone bodies produced
ketone bodies are produced in the liver when the liver’s glycogen stores have been depleted, and glujconeogeneis has been going on for a while to compensate during prolonged fasting. The body starts shifting away from gluconeogenesis and towards ketone body synthesis
what can/can’t ketones be used for
Ketones can be used as an energy source in the mitochondria of peripheral tissue during fasting.
They require mitochondria, so cannot be used in RBCs.
what are the counter-regulatory hormones that protect the body from hypoglycemia during fasting
Glucagon
Epinephrine
Cortisol
Growth Hormone
(low insulin)
what effect does decreased insulin have during fasting state
decreases peripheral glucose utilization, so your blood glucose level isn’t further depleted
it also sends a signal to increase hepatic gluconeogenesis and glycogenolysis to make more glucose to put sugar into the blood
what 3 molecules help to increase hepatic gluconeogenesis and glycogenolysis during fasting
Glucagon
Epinephrine
LOW insulin
they keep blood glucose levels high by increasing hepatic gluconeogensis and glyogenolysis to make more glucose to put sugar into the blood
“glucagon, for when glucose is gone”- it’s the first responder
what effect does cortisol and GH have during fasting state
they alter transcription of many genes to converse glucose during a fasting state to minimize further blood glucose loss during PROLONGED fasting.
Cortisol receptors are within the cytoplasm.
GH receptors are membrane-bound.
(glucagon and EPI as its back-up are the immediate responders to low blood glucose)
what is the major rate-limiting step in glycolysis
Phosphofructokinase-1
(PFK-1)
it catalyzes Fructose-6-Phosphate to Fructose-1,6-Bisphosphonate
anything inserted into glycolysis after this step will be quickly metabolized. this would be dietary fructose
(mannose, galactose, glucose, all enter higher up and are metabolized slower)
what does Arginase do
makes Urea and Ornithine from Arginine in urea cycle
Arginase deficiency is going to present with: High arginine (build up) spastic diplegia abnormal movements growth and developmental delay
MILD OR NO HYPERAMMONEMIA (vs other urea cycle disorders)
just remember Arginine is a key player in the urea cycle
what is lactose broken into
Lactose –>
Galactose + glucose
via Lactase
what is classic galactosemia
deficient GALT
galactose-1-phosphate uridyl transferase
(T = “traditional”/classic)
this is the severe form of galactosemia (vs mild GALK)
in the last step of galactose breakdown, Galactose-1-Phosphate cannot be converted to Glucose-1-Phosphate to enter the glycolysis/gluconeogenesis pathways
build up of galactose, so you get SEVERE symptoms in a newborn:
jaundice, vomiting, HSM, renal dysfunction, E coli sepsis, cataracts, hemolytic anemia
galactose can come from Lactose in breastmilk, so this presents early in life with SEVERE galactosemia
you need to switch to soy milk and exclude lactose and galactose from diet
what is galactokinase deficiency
deficient GALK
relatively mild condition where galactitol accumulates
because you can’t do the first step in converting galactose –> Galactose-1-Phosphate to make it back to the glucose pathway
symptoms will develop when an infant begins feeding because breast milk has lactose which goes to galactose + glucose
baby will get high galactose levels and infantile cataracts (can’t track objects or see your social smile)
galactoKINase deficiency is KIND enough to not be severe (vs severe GALT)
Run through Von Gierke disease
Type 1 Glycogen storage disease (VPCM)
defect in Glucose-6-Phosphatase
Glucose-6-Phoshate –> Glucose
it’s the last step in breaking glycogen into glucose in the liver
Presents with:
SEVERE fasting hypoglycemia (because liver can’t do gluconeogenesis)
very high glycogen in liver (glycogen is trapped)
high triglycerides, high uric acid (gout)
HEPATOMEGALY (things are stuck in the liver)
treat:
frequent oral glucose/cornstarch to avoid fasting hypoglycemia
avoid fructose and galactose (that have to be broken down to glucose to be used)
it’s the last step in glycogenolysis and glujconeogeneis, so both are impaired
Run through Pompe disease
Type 2 Glycogen Storage disease (VPCM)
defect in alpha-1,4-glucosidase ONLY IN LYSOSOMES
AKA Acid Maltase deficiency
cannot take Glycogen –> glucose in the lysosomes
“Pompe trashes the pump”- presents with CARDIOMEGALY
early death <2yo
pts will have normal blood glucose levels (problem is only in lysosomes)
lysosomes will be PAS (+) for glycogen
(hearts have 4 chambers, so remember alpha-1,4-glucosidase)
Run through Cori Disease
Type 3 Glycogen Storage Disease (VPCM)
defect in alpha-1,6-glucosidase “Debranching Enzyme”
mild form of Von Gierke normal blood lactate levels accumulation of Dextrin-like molecules (nubs) ketoacidosis hypotonia
“Your core has a 6-pack, so this is a 1,6 deficiency”
“a,b, C–>D for Cori –> Debranching and Dextrin-like accumulation”
“Cori Can’t Cleave”
Gluconeogenesis is intact (because you don’t always have to be
Run through Anderson’s disease
glycogen storage disease that isn’t one of the fab 4
defect in Branching enzyme
“A –> B, c,d” (like Cori–> Debranching)
“Anderson can’t Add”
Run through McArdle Disease and Hers disease
McArdle:
Type 5 glycogen storage disease (VPCM)
defect in Muscle glycogen phosphorylase (Myophosphorylase)
can’t complete the first step in muscle glycogen breakdown
present with: high muscle glycogen (stuck) painful muscle cramps myoglobinuria with exercise second-wind phenomenon due to increased muscle blood flow
Hers: Type 6 glycogen storage disease defect in HEPATIC glycogen phosphorylase Hepatomegaly (glycogen is trapped) poor growth symptoms improve with age
both have normal glycogen and normal glucose structure because the defect is in the very first step of glycogen breakdown
Run through essential fructosuria
defect in Fructokinase
Fructose –> Fructose-1-Phosphate
via fructokinase
benign, asymptomatic,
since Fructose is not trapped in cells-
it can go back to glucose via Hexokinase
positive Copper reduction test
“Hexokinase is “essentially” “kind” enough to make fructokinase asymptomatic”
Run through fructose intolerance
defect in Aldolase B
Fructose-1-Phosphate –> one of two:
DHAP –> Glycolysis
Glyceraldehyde –> glycerol
presents with fructose intolerance because:
Fructose-1-Phosphate gets trapped
you get hypoglycemia, jaundice, cirrhosis, vomiting
Treat:
don’t eat fructose or sucrose (glucose + fructose)
what is the energy source in aerobic conditions
pyruvate is converted to acetyl-CoA to enter the TCA cycle
what is the engird source in anaerobic conditions
when oxygen is depleted (exercising muscle),
pyruvate is converted to lactate
what is a limited molecule needed for glycolysis
NAD+
it is limited, and must be regenerated from NADH for glycolysis to continue
