Biochemistry- Metabolism (2) Flashcards
Describe the 1st step in the urea cycle
Carbamoyl phosphate synthetase I converts Co2 + NH3 (using N-acetylglutamate as a cofactor and converting 2ATP to 2ADP) to carbamoyl phosphate
this occurs in the mitochondria
Describe the 2nd step in the urea cycle
carbamoyl phosphate + ornithine to citrulline via orithine trancarbamylase
occurs in the mitochondria
Describe the 3rd step in the urea cycle
citrulline to argininosuccinate by adding aspartate and via argininosuccinate synthetase (ATP to AMP + PPi)
occurs in cytosol
Describe the 4th step in the urea cycle
argininosuccinate to arginine via argininosuccinase and giving of fumarate
occurs in cytosol
Describe the 5th step in the urea cycle
arginine to ornithine via arginase and converting water to urea to be transported to the kidneys for waste
occurs in cytosol
What is the purpose of the urea cycle?
to convert NH3 byproducts of amino acid catabolism to urea for excretion by the kidneys
Describe the initial transport of ammonia by alanine and glutamate through the body
Amino acids (NH3) are converted to a-ketoacids as a-ketoglutarate is converted to glutamate (NH3)
glutamate (NH3 carrier now) is then reconverted to a-ketoglutarate as pyruvate is converted to alanine (NH3)
All of this occurs in muscle
Describe the later transport of ammonia by alanine and glutamate through the body
alanine (NH3) then transports to the liver (Cahill cycle) and is reconverted to pyruvate as a-ketoglutarate is convertd to glutamate (NH3) to be converted to urea
Describe hyperammonia
Can be acqiured (e.g. liver disease) or hereditary (e.g. urea cycle enzyme deficiency) resulting in excess NH4+ which depletes a-ketoglutarate, leading to inhibiton of the TCA cycle
How is hyperammonia tx?
limit protein in diet.
give lactulose to acidify the GI tract and trap NH4+ for excretion
give rifaximin to decrease colonic ammoniagenic bacteria
give Benzoate or phenylbutyrate (both of which bind AAs and lead to excretion) to decrease ammonia levels
How does ammonia intoxication present?
tremor (ataxia), speech slurring, somnolence, vomiting
cerebral edema, vision blurring
What is the result of N-acetylglutamate synthase deficiency?
this is a required cofactor for carbamoyl phosphate synthetase I and its absence leads to hyperammonia. This presents in neonates as porly regulated respiration and body temp, poor feeding, developmental delay, intellectual disbaility (same presentation as phosphate synthetase I deficiency)
What is the most common urea cycle disorder?
ornithine transcarbamylase deficiency
Describe ornithine transcarbamylase deficiency
X-linked recessive (vs other urea cycle enzyme deficiencies which are AR) disorder that interferes with the body’s ability to eliminate ammonia.
How does ornithine trancarbamylase deficiency present?
Often very evident within the first few days of life, but may present later
the excess carbamoyl phosphate is converted to orotic acid (part of the pyrimindine synthesis pathway) so you will see elevated orotic acid in blood and urine, decreased BUN, symptoms of hyperammonia, but NO megaloblastic anemia (v.s. orotic aciduria)
What are the AA derivaties of phenylalanine?
Tyrosine (and Thyroxine), Dopa (and Melanin), Dopamine, NE, and Epi
What are the AA derivaties of tryptophan?
niacin (requires B6) and then NAD+/NADP+
serotonin (requires BH4, B6) and then melatonin
What are the AA derivaties of histidine?
histamine (requires B6)
What are the AA derivaties of glycine?
porphyrin (requires B6) and then heme
What are the AA derivaties of glutamate?
GABA (requires B6)
glutathione
What are the AA derivaties of arginine?
creatine, urea,
and nitric oxide (requires BH4)
Describe the 1st step of production of epinephrine
phenylalanine converted to tyrosine using phenylalanine hydroxylase (deficiency:PKU)(cofactor: BH4)
What two things can happen to tyrosine?
conversion to DOPA via tyrosine hydroxylase using BH4 or
conversion to homogentisic acid
What happens to homogentisic acid?
conversion to maleylacetoacetic acid via homogentisate oxidase (deficiency: alkaptonuria).
Note that maleylacetoacetic acid is then converted to fumarate to enter the TCA cycle
What happens to DOPA?
converted to either melanin via tyrosinase (deficiency: albinism) or
dopamine via DOPA carboxylase (cofactor:B6)
What drug can impair the action of DOPA carboxylase?
carbidopa
What happens to dopamine?
conversion to nor using vitC
(metabolic byproduct of dopamine is homovanilic acid)
How is nor converted to epi?
via phenylethanolamine-N-methyltransferase using SAM (cortisol promotes this)
What is the metabolic urine byproduct of nor?
normetanephrine to vanullylmandelic acid in urine
NOTE: epi is metbaolized to metanephrine to vanillylmandelic acid in urine as well
What cause phenylketonuria (PKU)?
deficiency of phenylalanine hydroxylase or decreased tetrahydrobiopterin (malignant PKU). Tyrosine becomes essential!
How does PKU present?
intellectual diability
growth retardation
seizures
fair skin
eczema
musty body odor
How is PKU tx?
decrease phenylalanine and increased tyrosine in diet
tetrahydrobiopterin supplementation
How common in PKU?
AR disease (1:10,000)
screening occurs by mandate 2-3 days after borth (even PKU pts will be normal at birth because of the presence of maternal enzyme during fetal life)
What causes the musty body odor in PKU?
disorder of aromatic amino acid metabolism
What common food should PKU pts avoid?
the artifical sweetener aspartame, which contain phenylalanine
What is maternal PKU?
What are the phenylketones?
phenylacetate, phenylpyruvate
What cause maple syrup urine disease?
blocked degradation of branched amino acids (isoleucine, leucine, valine) due to decreased a-ketoacid dehydrogenase (B1). causes increased a-ketoacids in the blood, especially those of leucine
How does maple syrup urine disease present?
severe CNS defects, intellectual disability, and death
How is maple syrup urine disease tx?
restriction of isoleucine, leucine, valine in diet
thiamine supplementation
What is the MOI of maple syrup urine disease?
AR
What does a congenital deficiency of homogentisate oxidase cause?
alkaptonuria (ochronosis), in which pigment-forming homogentisic acid accumulates in tissue
AR and usually benign
How does alkaptonuria (ochronosis) present?
dark CT tissue, brown pigmented sclera (below), urine turns black with prolonged exposure to air
may have disabling arthralgias (homogentisic acid is toxic to cartilage)
Again, how is homocysteine processed?
either:
conversion to methionine via homocysteine methyltransferase using B12 or
to cystathionine using serine + B12 and cystathionine synthase. Cystathionine is then converted to cysteine
Describe the main causes of homocysteinuria
All types are AR in nature:
- cystathionine synthase deficiency (tx with decreased methionine, increased cysteine supplements, and supplement B12 and folate in diet)
- decreased affinity of cystathionine synthase for pyridoxal phosphate (tx: supplemnt B6 and cysteine in diet)
- homocysteine methyltransferase (methionine synthase) deficiency (tx with supplementation of methionine in diet)
More about homocysteinuria and its findings
all forms/causes result in excess homocysteine in urine
Findings: elevated homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus (below), kyphosis, lens subluxation (downward and inward), thrombosis, and atherosclerotic formations (stroke and MI)
What causes hereditary cystinuria?
defect of renal PCT and interstinal amino acid transporter that prevents reabsorption of cysteine, ornithine, lysine, and arginine (COLA)
How might hereditary cystinuria present?
-precipitation of hexagonal cysteine stones in urine
What is the MOI of hereditary cystinuria?
AR (1:7000)
How is hereditary cystinuria diagnosed?
cyanide-nitroprusside test
How is hereditary cystinuria tx?
urinary alkalinization (e.g. potassium citratem acetazolamide) and chelating agents (e.g. penicillamine)
good hydration
How does glucagon binding to glucagon receptors and epi binding to B receptors affect glucose?
they both activate cAMP via adenylate cyclase which activates PKA, which activates glycogen phosphorylase kinase, which activates glycogen phosphorylase to convert to glycogen to glucose
How does epi binding to a receptors affect glucose?
it promotes calcium release from the ER, leading to increased calcium-calmodulin levels which also activates glycogen phosphorylase kinase to promote glycogen breakdown via glycogen phosphorylase
How does insulin binding to tyrosine kinase receptors affect glucose?
it activates both glycogen synthase which promotes glycogenogenesis and
protein phosphatase which inhibits glycogen phosphorylase
Note on the structure of glycogen
branches have a-1,6- bonds and linkages have a-1,4- links
How is glycogen processed in skeletal muscle?
glycogen undergoes glycogenolysis to glucose-1-P to glucose-6-phosphate, which is rapidly metabolized during exercise
How is glycogen processed in hepatocytes?
glycogen is stored and undegoes glycogenolysis to maintain BG at appropriate levels.
Describe the initial steps of formation of glycogen
glucose to G6P to G1P to UDP-glucose via UDP-glucose pyrophosphorylase
Describe the next steps of formation of glycogen
UDP-glucose to glycogen via glycogen synthase
What enzyme is responsible for adding the branching structure (a-1,6 bonds) on glycogen?
branching enzyme
What does glycogen phorphorylase do?
liberates G1P residudes off branched glycogen until 4 glucose units remain on a branch
How is glucose made from glycogen once glycogen phosphorylase liberates G1P residudes off branched glycogen until 4 glucose units remain on a branch?
debranching enzyme (4-a-D-glucanotransferase) moves 3 molecules of G1P from the branch to the linkage
Then a-1,6-glucosidase cleaves off the last residue, liberating glucose
What is ‘limit dextrin’?
refers to the one to four residues remaining on a branch after glycogen phorphorylase has already shortened it
What are the main glycogen storage diseases?
- Von Gierke disease (type I)
- Pompe Disease (type II)
- Cori Disease (type III)
McArdle Disease (type V)
Very Poor Carbohydrate Metabolism
What causes Von Gierke disease (type I)?
deficiency of Glucose-6-phosphatase
What are the findings of Von Gierke disease (type I)?
severe fasting hypoglycemia
elevated glycogen in liver
elevated blood lactate, TAGs, uric acid
hepatomegaly
What is the MOI and tx of Von Gierke disease (type I)?
MOI: AR
Tx: frequent oral glucose/cornstarch; avoidance of fructose and galactose
What causes Pompe disease?
lysosomal a-1,4-glucosidase (acid maltase) deficiency
What are the findings with Pompe disease?
-cardiomegaly
hypertrophic cardiomyopathy
exercise intolerance
early death
What is the MOI of Pompe disease?
AR
What causes Cori Disease (a milder form of Von Gierke disease with normal blood lactate levels)?
debranching enzyme (a-1,6-glucosidase) deficiency
Notes about Cori Disease
AR MOI
Gluconeogenesis is intact
What causes McArdle disease (type V)?
skeletal muscle glycogen phorphorylase (myophosphorylase) deficiency
What are the findings of McArdle disease (type V)? Tx?
elevated glycogen in muscle, but muscle cannot break it down leading to painful muscle cramps, myoglobinuria (red urine) with strenuous exercise and arrhythmia from electrolyte abnormalities
AR; tx with vitB6
T or F. All glycogen storage diseases (of prevelance) are AR
T.
What are the sphingolipidoses (lysosomal storage diseases)?
Fabry disease
Gaucher disease
Niemann-Pick disease
Tay-Sachs disease
Krabbe disease
Metachromatic leukodystrophy
What causes Fabry disease?
a-galactosidase A
How does Fabry disease present?
accumulation of ceramide and trihexoside cause peripheral neuropathy of hands and feet, angiokeratomas, and CV/renal disease
What is the MOI of Fabry Disease?
XR
What causes Gaucher disease?
deficiency of glucocerebrosidase (B-glucosidase)
How does Gaucher disease present?
accumulation of glucocerebroside cause hepatosplenomegaly, pancytopenia, osteoporosis, aseptic necrosis of femur, bone crises
What are these?
Guacher cells (lipid laden macrophages resembling crumpled tissue paper)
What is the MOI and tx of Guacher disease?
MOI: AR
Tx: recombinant glucocerebrosidase
What causes Niemann-Pick disease?
deficiency of spingomyelinase causing accumulation of sphingomyelin
How does Niemann-Pick disease (MOI:AR) present?
progressive neurogeneration
hepatosplenomegaly
‘cherry red’ spot on macula
foam cells (lipid-laden macrophages) (below)
What causes Tay-Sachs disease?
deficiency of hemosaminidase A leading to accumulation of GM2 ganglioside (MOI: AR)
How does Tay-Sachs disease (MOI: AR) present?
progressive neurogeneration
developmental delay
‘cherry red’ spot on macula
lysosomes with onion skin
NO hepatosplenomegaly (vs. Neimann Pick)
What causes Krabbe Disease?
deficiency of galactocerebrosidase causing accumulation of galactocerebroside and psychosine (MOI: AR)
How does Krabbe disease present?
Peripheral neuropathy
developmental delay
optic atrophy
globoid cells (below)
What cause Metachromatic leukodystrophy? MOI?
deficiency of arylsulfatase A causing accumulation of cerebroside sulfate (MOI: AR)
How does present metachromatic leukodystrophy present?
central and peripheral demyelination with ataxia, dementia
What are the mucopolysacchardidoses?
Hurler syndrome (AR)
Hunter syndrome (XR)
What causes Hurler syndrome?
deficiency of a-K-iduronidase causing accumulation of heparan sulfate and dermatan sulfate
How does Hurler syndrome (MOI: AR) present?
developmental delay
gargoylism
airway obstruction
corneal clouding
hepatosplenomegaly
What causes Hunter syndrome (MOI: XR)? Presentation?
deficiency of iduronate sulfatase causing accumulation of heparan sulfate and dermatan sulfate
presents with a milder Hurler syndrome plus added aggressive behavior, and no corneal clouding
There is an increased incidence of Tay-Sachs, Niemann-Pick, and somes forms of Gaucher disease in who?
Ashkenazi Jews
Processing of spingolipids and mucopolysacchardies
sulfatides to galactocerebroside (metachromatic leukodystrophy) to ceramide (krabbe)
GM2 to GM3 (Tay Sachs) to glucocerebroside to ceramide (Gaucher)
ceramide trikexoside to glucocerebroside (Fabry)
sphingomyelin to ceramide (Niemann Pick)
Describe fatty acid synthesis
FA synthesis involves transport of citrate from the mitochondrila matrix to the cell cytoplasm via the citrate shuttle where ATP citrate lyase converts it to acetyl-CoA and then the addition of CO2 and biotin produce malonyl-CoA which ends up as FAs
Where does fatty acid synthesis predominantly occur?
liver, lactating mammary glands, and adipose tissue
Describe long chain fatty acid degradation
FAs + CO2 are converted to fatty acyl-CoA via fatty acid CoA synthase which is then shuttled to the mitochondrial matrix via the carnthine shuttle and converted acyl-CoA via acyl CoA dehydrogenases (B-oxidation).
Acyl-CoA is broken down into ketone bodies and TCA cycle intermediates
What is systemic primary carthine deficiency?
inherited defect in transport of LCFAs into the mitochondria causing toxic accumulation leading to weakness, hypotonia, and hypoketotic hypoglycemia
Describe medium chain acyl-CoA dehydrogenase deficiency
AR disorder of FA oxidation marked by inability to break down fatty acids into acetyl-CoA resulting in accumulation fo 8-to 10- carbon fatty acyk carnithines in the blood and hypokinetic hypoglycemia
May present in infancy or early childhood with vomiting, lethargy, seizures, coma, and liver dysfunction
How is medium chain acyl-CoA dehydrogenase deficiency tx?
avoiding fasting
In the liver FAs and AAs are metabolized to acetoacetate and B-hydroxybutyrate (to be used in brain and muscle)
In prolonged starvation and diabetic ketoacidosis, oxaloacetate is deplated for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate. Both processes cause a builup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies
Breath smells like acetone (fruity odor)
Urine test for ketones does not detect B-hydroxybutyrate
What are the priorities in times of fasting?
supply sufficient glucose to the brain and RBCs and to preserve glucose
What processes are active in the fed state?
glycolysis and aerobic respiration. Insulin stimulates storage of lipids, proteins, and glycogen
What processes are active during fasting (between meals)?
hepatic glycogenolysis (major); hepatic gluconeogenesis, adipose release of FFA (minor)
Glucagon and epi stimulate use of fuel reserves
What processes are active during starvation (1-3 days)?
blood glucose is maintained by hepatic glycogenolysis, adipose release of FFA, muscle and liver, which shift fuel use from glucose to FFA, and hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA (from odd-chain FFA- the only TAG components that contribute to gluconeogenesis)
Note that glycogen reserves run out after day 1 and RBCs lack mitochondria and therefore cannot use ketones
What processes are active during starvation (3+ days)?
adipose stores (ketone boies become the main source of energy for the brain). After these are depleted, vital protein degradation accelerates, leading to organ failure and death
What are the main uses of cholesterol?
cholesterol is needed to maintain cell membrane integrity and to synthesize bile acid, steroids and vitD
Notes about cholesterol synthesis
The rate-limiting step is catalyzed by HMG-CoA reductase (induced by insulin; inhibited by statins), which convert HMG-CoA to mevalonate.
2/3 of plasma cholesterol is esterfied by lecithin-cholesterol acyltransferase (LCAT)
What is the function of pancreatic lipase?
degradation of dietary TAGs in the small intestine
What is the function of lipoprotein lipase?
degradation of TAGs circulating in chylomicrons and VLDLs. Found in the vascular endothelial surface
What is the function of hepatic TAG lipase?
degradation of TAGs remaining in IDL
What is the function of hormone-sensitive lipase?
degradation of TAGs stored in adipocyte
What does apolipoprotein E do?
mediates remnant uptake. Found in chylomicrons, chylomicron remnants, VLDL, IDL, and HDL
What does apolipoprotein A-1 do?
activates LCAT. Found in chylomicrons and HDL
What does apolipoprotein C-II do?
lipoprotein lipase cofactor found in chylomicrons, VLDL, and HDL
What does apolipoprotein B-48 do?
mediates chylomicron secretion found in chylomicrons and chylomicron remnants
What does apolipoprotein B-100 do?
binds to the LDL receptor and found in VLDL, IDL, LDL
What are lipoproteins?
composed of varying proportions of cholesterol, TAGs, and phospholipids. LDL and HDL carry the most cholesterol
LDL carries cholesterol from liver to tissues
HDL transports cholesterol from the periphery to the liver
What is the purpose of chylomicrons?
delivery of dietary TAGs to peripheral tissue. Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TAGs. Secreted by intestinal epithelial cells
What is the purpose of VLDL?
delivers hepatic TAGs to peripheral tissue. Secreted by liver
What is the purpose of IDL?
Formed in the degrdation of VLDL. Dellivers TAGs and cholesterol to liver
What is the purpose of LDL?
Delivers hepatic cholesterol to peripheral tissues. Formed by hepatic lipase modifiction of IDL in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis
What is the purpose of HDL?
Mediates reverse cholesterol transport from periphery to the liver. Acts as a repository for apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism). Secreted from both liver and intestine.
Alcohol increases synthesis
Describe familial hyperchylomicronemia
AR disorder caused by LPL deficiency or altered apolipoprotein C-II leading to elevated chylomicrons, TAGS, and cholesterol
How does familial hyperchylomicronemia present?
pancreattis
hepatosplenomegaly
and eruptive/pruritic xanthomas (no increased risk for atherosclerosis).
Forms creamy layer in supernatant
What is familial hypercholesterolemia?
AD disease caused by absence or defective LDL receptors leading to increased LDL and cholesterol (heterozygotes have cholesterol levels of ~300mg/dL and homozygotes (very rare) have cholesterol of around 700+mg/dL.
causes accelerated atherosclerosis (may have MI before age 20), tendon (Achilles) xanthomas, and corneal arcus
Describe hyperTAGemia
AD syndrome of hepatic overproduction of VLDL leading to increased levels of VLDL and TAGs
HyperTAGemia over 1000mg/dL can cause acute pancreatitis
