Biochem 4 Flashcards
Phenylketonuria path
Decreased Phe hydroxylase or dec. tetrahydrobiopterin cofactor (malignant PKU)
What is malignant PKU?
Neonatal PKU due to tetrahydrobiopterin (BH4) deficiency
Phenylketonuria labs
excess phenylketones in urine
PKU presentation
MR, growth retardation, seizures, fair skin, eczema, musty body odor.
PKU tx
decrease Phe and increase tyrosine in diet
what amino acid is essential in PKU
tyrosine before essential
PKU genetics
aut. rec. (1/10,000)
When does PKU appear
2-3 days after birth (enzyme from mother)
What are the phenylketones
phenylacetate, phenyllactate, and phenylpyruvate
Maternal PKU path and presetnation
lack of proper diet therapy during pregnancy. Infant has microcephaly, intellectula disability, growth retardation, congenital heart defects.
Alkaptonuria alternate name
Ochronosis
Homocystinuria types and genetics
3 types. All aut. rec.
- Cystathionine synthase deficiency
- Decreased affinity of cystathionine synthase for pyridoxal phosphate
- Homocysteine methyltransferase (methionine synthase) deficiency
Homocystinuria presentation
All forms result in excess homocysteine. MR, osteoporosis, tall stature, kyphosis, lens subluxation downward and inward, thrombosis, and atherosclerosis (stroke and MI)
Homocystinuria labs
elevated homocysteine in urine
Cystathionine synthase deficiency tx
lower methionine, increase cysteine, increase b12 and folate in diet
decreased affinity of cystathionine synthase for pyridoxal phosphate tx
increased b6 and cysteine in diet
homocysteine methyltransferase deficiency tx
increase methionine in diet
why does adding cysteine and methionine help with homocystinuria………
Not because it reverses any issues with homocysteine, it just helps in supplying methionine and cysteine which are needed in our bodies!
Cystinuria genetics and path
Aut. rec. (Common 1:7,000) hereditary defect of renal PCT and intestinal amino acid transporter for Cysteine, ornithine, Lysine, and Arginine (COLA)
Cystinuria presentation
Excess cystine in urine can lead to precipitation of hexagonal cystine stones
Cystinuria labs
urinary cyanide-nitroprusside test is diagnostic
Cystinuria tx
urinary alkalinization (e.g. potassium citrate, acetazolamide) and chelating agents increase solubility of cystine stones; good hydration
What is a cystine bond
2 cysteines connected with a disulfide bond
Maple syrup urine disease genetics and path
Aut. rec. Blocked degradation of branched amino acids (isoleucine, leucine, valine) due to decreased alpha-ketoacid dehydrogenase (B1). Causes increased alpha-ketoacids in blood especially leucine.
Maple syrup urine disease presentation and treatment
Causes severe CNS defects, intellectual disability, death.
I Love Vermont maple syrup (Isoleucine, leucine, valine)
restrict BCAAs and supplment thiamine
What pathway does glucagon activate
Binds glucagon receptor in liver activating adenylate cyclase leading to increased cAMP activating Protein kinase A activating glycogen phosphorylase kinase phosphorylating glycogen phosphorylase forming more glucose. Protein Kinase A also inhibits glycogen synthase.
What does PKA end up doing
Activates glycogen phosphorylase kinase and blocks glycogen synthase
What pathways does epinephrine activate
Binds beta-receptor in liver and muscle to activate the adenylate cyclate pathway like glucagon. In the liver, it also releases calcium from the ER activating glycogen phosphorylase kinase. Calcium-calmodulin is activated in muscle contraction and also activates glycogen phosphorylase kinase.
What pathway does insulin activate
Binds Tyrosine kinase dimer receptor and activates glycogen synthase and protein phosphatase to block glycogen phosphorylase.
What are the bonds in glycogen
alpha-(1,6) bonds for branches and linkages are alpha-(1,4) bonds
Glycogen metabolism in skeletal muscle
Glycogenolysis to glucose-1-P to glucose-6-P to be used up
How is glycogen cleaved up
glycogen phosphorylase cleaves off glucose-1-P off branches until there are 4 glucoses left. Then 4-alpha-D-glucanotransferase moves 3 glucoses off the branch to the linkage. Then alpha-1,6-glucosidase cleaves off the last glucose-1-P on the branch
What is a limit dextrin
The 1-4 residues on a branch after glycogen phosphorylase has already shortened it
What are the debranching enzymes
4-alpha-D-glucanotransferase and alpha-1,6-glucosidase
How to build glycogen
UDP-glucose is formed by UDP-glucose pyrophosphorylase from glucose-1-P.
What is acid maltase
In lysosomes, it is alpha-1,4-glucosidase. A small amount of glycogen is degraded in lysosomes.
Glycogen storage diseases mnemonic
Very Poor Carbohydrate Metabolism (Von Gierke, Pompe, Cori, McArdle)
Von Gierke disease (type 1) presentation
Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, hepatomegaly
Von Gierke path and genetics
aut. rec. glucose-6-phosphatase absence
Von Gierke tx
frequent oral glucose/cornstarch; avoid fructose and galactose
Why avoid fructose and galactose in Von Gierkes?
Galactose, fructose, and glycerol are metabolized to lactate causing metabolic acidosis.
Pompe disease presentation (type II)
Cardiomyopathy and systemic findings leading to early death
Pompe path
Lysosomal alpha-1,4-glucosidase (acid maltase)
Pompe genetics and mnemonic
Aut. rec.
Pompe trashes the Pump (heart, liver, and muscle)
Cori disease (type III) presentation
Milder form of type I with normal blood lactate levels.
Cori disease path
debranching enzyme (alpha-1,6-glucosidase). GNG is intact
Cori diease genetics
aut. rec.
McArdle disease (type V) presentation
Increased glycogen in muscle but cannot break it down, leading to painful muscle cramps, myoglubinuria (red urine) with strenuous exercise, and arrhthmia from electrolyte abnormalities
McArdle disease path
Skeletal muscle glycogen phosphorylase (myophosphorylase)
McArdle disease genetics
Autosomal recessive. (McArdle=Muscle)
What is the basis of lysosomal storage diseases
Deficiency in one of many lysosomal enzymes. Results in accumulation of abnormal metabolic products)
fabry disease enzyme and substrate
alpha-galactosidase A builds up Ceramide trihexoside
Gaucher dz enzyme and substrate
glucocerebrosidase (beta-glucosidase) builds up glucocerebroside
niemann-pick disease enzyme and substrate
Sphingomyelinase and sphingomyelin
Tah-Sachs disaease enzyme and substrate
hexosaminidase A and GM2 ganglioside (AR)
Krabbe disease enzyme and substrate
galactocerebrosidase and galactocerebroside, psychosine
Metachromatic leukodystrophy enzyme and substrate
arylsulfatase A and cerebroside sulfate
Hurler syndrome enzyme and substrate
alpha-L-iduronidase and heparan sulfate, dermatan sulfate
Hunter syndrome enzyme and substrate
iduronate sulfatase and heparan sulfate, dermatan sulfate
Mnemonic for lysosomal storage diseases
- No man picks (Niemann-Pick) his nose with his sphinger (sphinogomyelinase)
- Tay-SaX lacks heXosaminidase
- Hunters see clearly (no corneal clouding) and aggressivly aim for the X (X-linked recessive)
Which lysosomal storage diseases are higher in Ashkenazi Jews
Tay-Sachs, Niemann-Pick, and some forms of Gaucher disease
What makes acyl-CoA
Fatty acid CoA synthetase
What blocks the carnitine shuttle
Malonyl CoA
Where are fatty acids synthesized
In the cytosol
What is the basic pathway for fatty acid synthesis
citrate from mitochondrial matrix moves via the citrate shuttle to produce acetyl-CoA via ATP citrate lyase, combines with CO2 (biotin) to produce malonyl-CoA which provides 2 carbons to fatty acid synthesis
What is the end product of fatty acid synthesis
Palmitate a 16C FA
Metabolism of ketone bodies
in liver, fatty acids and amino acids broken down to acetoacetate and beta-hydroxybutyrate (used in muscle adn brain)
What happens in prolonged starvation and DKA
OAA depleted for GNG.
What happens in alcoholism
Excess NADH shunts oxaloacetate to malate.
What happens in both starvation, DKA, and alcoholism
Buildup acetyl-CoA which shutns glucose and FFA towards production of ketone bodies
Urine test for ketones doesn’t detect what
Beta-hydroxybutyrate
When starving for 1-3 days what happens to energy usage
Muscle and liver shift to use FFA from glucose
Hepatic GNG sources
peripehral tissue lactate and alanine and adipose tissue glycerol and propionyl-CoA (from odd-chain FFA)
how long to deplete glycogen reserves
After day 1
Can RBCs use ketones?
No, they lack mitochondria
Starvation after 3 days energy stores
Adipose stores (ketone bodies become the main source of energy for the brain)
Cholesterol synthesis rate limiting step
Catalyzed by HMG-CoA reductase (induced by insulin), which converts HMG-CoA to mevalonate. 2/3 of plasma cholesterol is esterified by lecithin-cholesterol acyltransferase (LCAT)
What do statins to
Competitively and reversibly inhibit HMG-CoA reductase
Pathway of chylomicrons
Broken down by lipoprotein lipase into chylomicron remnants which are broken down further by LPL and hepatic TG lipase and then taken up by liver remnant receptors.
Pathway of VLDL
VLDL broken down by LPL to release FFA to adiopose and peripheral tissues with LDL receptors to produce IDL. IDL is broken down by HL to LDL which can be taken up by peripheral tissues or brought back to liver.
What is hormone sensitive lipase
In adipocytes and breakdown TG
Pathway of a nascent HDL
Transformed by LCAT (lecithin-cholesterol acyltransferase) (esterifies cholesterl) to form mature HDL which can return to liver or through CETP (cholesterol ester transfer protein) which mediates transfer of cholesterol esters to other lipoprotein particles like VLDL, IDL, and LDL
What is the purpose of CETP?
It transports cholesterol esters to LDL and VLDL and accepts TGs. CETP inhibitors increase HDL and lower LDL levels, but the effect is useless.
What is the purpose of LCAT?
LCAT allows for the formation of mature HDL. It turns free cholesterol from the gut and peripheral tissues into the esterified form which can be carried by HDL back to the liver! or to be processed by CETP to add cholesterol to the other lipoproteins.
ApoE function
Mediates remnant uptake
ApoA-I function
Activates LCAT
ApoC-II function
Lipoprotein lipase cofactor
ApoB-48 function
Mediates chylomicron secretion
ApoB-100 function
Binds LDL receptor.
What lipoproteins carry most cholesterol
LDL and HDL
What does LDL and HDL do
Both transport cholesterol, LDL to tissues and HDL back to liver
Chylomicron source
Delivers dietary TGs to peripheral tissue. Secreted by intestinal epithelial cells.
VLDL function
delivers Hepatic TGs to peripheral tissue. secreted by liver.
IDL function
Delivers TGs and cholesterol to liver
LDL function
delievers hepatic cholesterol to periphery. Formed by hepatic lipase modification of IDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis.
HDL function
Repository for apoC and apoE which are needed for chylomicron and VLDL metabolism. Secreted from both liver and intestine. Alcohol increases synthesis.
Type I: Hyper-chylomicronemia presentation
Increased chylomicrons, TG, and cholesterol
Type IIa: familial hyper-choletserolemia presentation
Increased LDL, choelsterol
Type IV: hypertriglyceridemia presentation
Increased VLDL and TG
What is tetrahydrobiopterin
BH4. Used in aromatic amino acid hydroxylase enzymes. Made from guanosine triphosphate.
