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353 Cards in this Set

  • Front
  • Back
Where are the major sites of heme synthesis
bone marrow and liver, does occur in virtually all cells EXCEPT mature erthrocytes
Signs of a metabolic disorder include
illness, vomiting, poor growth/FTT, DD/MR, regression, hypo/hypertonia, seizures, unusual ordors, corase facial features
What are the two structural comonents of heme
Fe2+ and protoporphyrin IX
What are the essential amino acids?
Leucine, Lysine, Histidine, isoleucine, phenylalanine, Threonine, tryptophan, Methionine, Valine

Hint: Leuvly LaYdies Have irresistible Phanties, THat, THey, Must Vacate
Porphyrins can have substituent groups attached to the pyrrole rings that modify what proteins they associated with. There are three different substituents and fifteen positional isomers. What are the three possible substituents? Which isomer is of physiological significance
substituents= methyl, vinyl, propionyl
Significant= ferroprotoporphyrin
Signs of a metabolic disorder mimic
serious infection, must be ruled out
What is the difference between heme and hemin
Oxidation state of iron
Fe2+=ferroprotoporphyrin IX
Fe3+=ferriprotoporphyrin IX
what is the required co-factor for aminotransferases
PLP (B6 derivative)
In general, where do the steps of heme biosynthesis occur
1st and last three are in the mitochondrion, intermediate are in the cytosol
NBS criteria inculde
Disease-high incidence, available interventions
Tests- simple, reliable, accurrate, cheap
Program-universal and uniform, follow-up, Dx, management, and Tx, favorable risk/benefit ratio
What is the commited step of heme biosynthesis? How is it regulated
Commited step is ALAS. Regulated kinetically by glycine levels. ALAS 1 inhibited by excess heme at transcription, translation, and translocation

Note that heme biosynthesis in erthyroid cells occurs via ALAS 2 which is NOT inhibited by heme
Where are the conditionally essential amino acids required?
under conditions of growth or diesease, arginine is required for neonates
What is the first step of heme biosynthesis? Where does it occur?
Glycine and succinyl-CoA condense to form ALA (5-aminolevulinate). This occurs via ALAS 1 (hepatic) or ALAS 2 (erthroid)
List every test on the WI NBS pannel
Just kidding :-)
hope you're enjoying the flashcards. Good luck studying!!
What is the second step of heme biosynthesis? Where does it occur?
(just made ALA)
Occurs in the cytosol
Two ALAs condense to form 1 porphobilinogen (PBG), catalyzed by ALA dehydratase (ALAD)
Compare the lysosomal and ubiquitin proteasome protein degradation systems in terms of:
lysosome-lipid bilyaer
UP=cylindrical proteasome
How does lead interfere with heme
(lead poisonin mimics acute porphyrias)
1. ALAD-requires zinc complexed to active cysteine, lead displaces zinc and eliminates catalytic activity
2. Ferrochelatase
Treatment of PKU includes
1. limit phenylalanie
2. provide medical food
3. provide low protein foods to sup. diet
4. provide vitamin and mineral supplements
What is the third step of heme biosynthesis? Where does it occur?
(Just made PBG)
Occurs in the cytosol
Four PBGs condense head to tail to form hydroxymethylbilane which cyclizes to uroporphyrinogens I and III (UROS directs the reaction to III)
How is alanine synthesized
ALT transfers an amino group from glutamate onto pyruvate
What is the purpose of UROS in the heme biosynthetic pathway
Hydroxymethylbilane (from 4x PBG condensation) can spontaneously cyclize to uroporphyrinogen I which is not the correct sterochemical form. UROS directs the reaction so that uroporphyrinogen III is made instead.
Which AA should be supplemented as part of PKU tx
What is the 4th step of heme biosynthesis? Where does it occur?
(just made uroporphyrinogen III)
The acetate side chains on uroporhyrinogen III are decarboxylated to methyl groups to yeild coprophorphyrinogen III. This occurs in the cytosol and is catalyzed by UROD
What does alanine aminotranferase do?
Interconverts alanine an pyruvate by transfering the amino group to a-KG forming glutamate
What is the 5th step of heme biosynthesis? Where does it occur?
(just made coproporphyrinogen III)
Occurs in the matrix. Coproporphyrinogen III is converted to protoporphyrinogen IX by CPO. Propionic acid side chains are converted to vinyl groups.
What is the cause of Maple Syrup Urine Disease (MSUD)
disorder of branched chain amino acid degradation,
defective branched chain alpha ketoacid dehydrogenase complex (BCKAD)
What is the 6th step of heme biosynthesis? Where does it occur?
(just made protoporphyrin IX)
Protoporphyrinogen IX is converted to protoporphyrin IX by PPO. This occurs in the mitochondrion.
How is glutamate synthesized? (2 ways)
1. Amino transferases transfer an amino group onto a-KG
2. Free ammonia is added to a-KG via glutamate dehydrogenase
What is the final step of heme biosynthesis? Where does it occur?
Just made protoporphyrin IX
Fe 2+ is inserted by ferrochelatase. Note that this enzyme is inhibited by heme, lead, and iron deficiency.
How should MSUD be treated
-limit branched chain AAs (leucine, isoleucine, valine) by restricting complete protein
-agressive Tx when sick, use IV D10,
-liver transplant
Give three examples of species that modify ferrochelatase activity
iron deficiency-inhibits
Risk factors associated with atherosclerosis
Resistance to insulin
Pressure (high blood pressure)
When will person with a porphyria exhibit cutaneous photosensitivity
only when the block results in build up of cyclic tetraphyrroles. If the deficiency is before this step (before PBG makes uroporphyrinogen) there will be no generation of ROS.
Medical goals for PKU treatment incdlue
-Decrease PHE
-Maintain overall health while on restricted diet
-new option = bipterin therapy, most efffective for 2% w/ THB deficiency
Will a defiency in ALAD or PBGD cause photosensitivity
No. These steps occur prior to the formation of porphyrins so there is no increases in ROS due to UV irradiation
How is aspartate synthesized
AST transfers ammonia onto OAA
Which two enzymes in the heme biosynthetic pathway will lead inhibit? What products will accumulate in the urine?
Ferrochelatase and ALAD
Protoporhyrin and ALA will accumualte
What does asparate amino transferase do?
Interconverts aspartate and OAA by transfering the amino group to a-KG forming glutamate
Which enzyme defiency causes Variegate porphyria? What accumulates in the urine? Is there photosensitivity?
Variegate porphyria is an acute disease caused by a deficiency in protoporphyrinogen oxidase (PPO). Protoporphyrinogen IX and other proxmial intermediates accumulate in the urine. Patiens are photosensitive because porphyrins have been made.
How is Asparagine synthesized
Aspartate is converted to asparagine by asparagine synthetase using glutamine as a source of nitrogen
Jaundice results from an accumulation of
bilirubin, an orange pigment
Compare the lysosomal and ubiquitin proteasome protein degradation systems in terms of:
type or protein degraded
lysosome= extracellular and intracellular from cytosol

UP=intracellular from cytosol and nucelus
Where deos the majority of heme catabolism occur
In senescent erthrocytes, dead RBCs are taken up by the reticuloendothelial system (liver and spleen)
How is tyrosine synthesized
Phenylalanine is hydroxylated by phenylalanien hydroxylase
Describe the first reaction of heme catabolism where the ring is opened. Where does this occur?
Ferroprotoporphyrin IX ring is cleaved at the a-methene bridge by microsomal heme oxygenase. Uses NADPH. The second step invovles the non-enzymatic oxidation by O2 and release of CO. This releases iron and leaves biliverdin which is green.
The ring opening occurs in the macrophage.
What does branched chain amino acid transferase do (what AA's does it act on)
transfers teh amino group from valine, isoleucine, and leucine to a-KG forming glutamate
What happens to the biliverdin that was generated after heme ring opening and iron release? Where does this occur?
Biliverdin is converted to bilirubin by biliverdin reductase using NADH or NADPH. This occurs in hte macrophage. Note that bilirubin is less polar and can cross the membrane into the blood.
What is the source of tetrahydrofolate
It is the reduced form of the vitamin folate
How does bilirubin generated by biliverdin reductase reach the liver?
Bilirubin binds to serum albumin which transports it from the spleen and bone marrow to the liver
List the 5 major classes of hormones and the number of carbons they contain
1. progestins-21
2. glucocorticoids-21
3. mineralcorticoids-21
4. androgens-19
5. estrogens-18
What happens to bilirubin after it arrives at the liver on albumin.
Bilirubin dissociates from albumin and then associates with ligandins to temporary store it in the hepatocye.
What are the two ways serine can be synthesized?
1. From 3-phosphoglycerate, a glycolytic intermediate

2. From glycine with the addition of a methyl group from 5, 10 Me THF
Efficient excretion of bilirubin from hepatocytes depends on its conversion to polar conjugates. How does this occur?
UDPGT (ER) transfers glucuronic acid onto bilirubin yielding BMG or BDG.
How is ALT distributed amongst tissues? how can this be used diagnostically
-Much higher in liver than other tissues
-Elevated in blood of pts with liver disease
-Extremely high with viral hepatitis, ischemic liver injury, toxin/drug induced liver injury, prolonged hypotension, acute heart failure
What is the purpose of MOAT in bilirubin excretion
MOAT transfers the conjugated bilirubin (BMG or BDG) across the liver canalibular membranes
How does serine serve as a source of 1 carbon units
Serine is converted to glycine by serine hydroxymethyl transferase and the methyl group is donated to THF
What happens to conjugated bilirubin after it reaches the intestine
It is efraded by intestinal bacteria into urobilinogen products which are deconugated.
Compare the lysosomal and ubiquitin proteasome protein degradation systems in terms of:
Both used endo and exo peptidases but the ezymes are unqiue to each system
What happens to the urobilinogen products that are made from conjugated bilirubin in the intestine by bacteria (3)
1. oxidized to stercobilin (brown) and excreted in feces
2. Participates in the enterohepatic urobilinogen cycle
3. Transported in blood to kidney and converted to urobilin (yellow) and excreted in the urine
What are the two ways to synthesize glycine
1. Take a methyl group off serine and put it on THF via serine hydroxylmethyl transfersase

2. Glycine cleavage enzyme converts CO2 and NH4 and a methyl group from 5,10 Me THF to glycine
What test is used to determine serum bilirubin
van den bergh assay
(water soluble conjugated bilirubin reacts rapidly to give direct value, in methanol both forms react giving total. Subtracting direct from total gives indirect)
How is AST distributed amongst tissues? how can this be used diagnostically
-found at similar concentrations in most cells
-elevated in pts with liver/kidney/ CV disease
-extemely high with prolonged hypotension, MI
Why are neonates vulnerable to jaundice
Delayed maturation of UDPGT enzyme results in insufficient conjugation and impaired excretion of bilirubin
Which 4 molecules serve as donors to the folate pathway?
1. serine (via serine hydroxymethyl transferase)
2. glycine (degradation direction via glycine clevage enzyme)
3. histidine
4. formate
What type of hyperbilirubinemia is neonatal jaundice
How does insulin resistance contribute to dyslipidemia
-increased lipolysis=> increased TG/FFA
-less active lipoprotein lipase, don't take up TGs from VLDL and chylomicrons, further promotes high FFA
-stabilization of ApoB, incrased VLDL=>remodeling
Untreated neonatal jaundice can lead to?
How is it treated?
kernicterus, a discoloration of the basal ganglia which can lead to neurological problems

Tx with phototherapy to change configuration of bilirubin to an excretable form.
Expalin how one carbon donors enter the folate pathway
The donors are metabolised to 5,10 MeTHF and then converted to 5-Me THF by methylene THF reductase in a unidrectional direction
Inherited unconjugated hyperbilirubinemias are the result of a disorder in which enzyme
note that these span a spectrum of disorders from Crigler-Najar type I, Type II and Gilbert
In general, how can aminotransferses be used as diagnostic tools
-normally serum contains low levels
-upon tissue injury the enzymes are released into the vascular system
-levels of AT's, LDH and CK are diagnostic markers for tissue damage
What type of hyperbilirubinemia is Crigler-Najjar/ Gilbert's
unconjugated, results from UDPGT deficiency
Explain how the two one carbon pathways (folate and SAM) are interconnected
Folate pathway provided 5-MeTHF that the SAM cycle needs to convert Methionine back to homocysteine. This conversion generates the THF that the folate cycle needs. This is the onlyway that 5-Me THF can be recycled
Give two examples of disorders resulting in conjugated hyperbilirubinemia
1. Dubin-Johnson=defective MOAT
2. Rotor syndrome
Compare the lysosomal and ubiquitin proteasome protein degradation systems in terms of:
lysosomal=non-specific except during starvation, type I diabetes, and cachexia where it recognizes specific amino acid motifs
UP= E2's and 3's determine specificity
Hemolytic jaundice is the result of build up of what form of bilirubin
unconjugated (indirect), excessive ertythrocyte destruction results in the formation of bilirubin the amounts exceeding the conjugating ability of the liver. Free bilirubin increases in the plasma
What are the precursors of purines
aspartate, glycine, formate in the form of 5-Fo THF
Obstructive jaundice is the result of build up of what form of bilirubin
Conjugated (direct)-results from obstruction of the bile ducts, conjugation is working fine but the conjugated bilirubin can't get to the intestine so it appears in the plasma
Which enzymes release free ammonia?
dehydratases and lyases
(threonine dehydrtase, serine dehydratase, histidine ammonia lyase)
Hepatocellular jaundice is the result of build up of what form of bilirubin
Unconjugated (indirect)-damage to the liver impair's its ability to conjugate and excrete circulating bilirubin so the unconjugated form builds up
What are the precurors of the pyrimidines
Aspartate and glutamine (as carbamoyl phosphate)
Findings from the NHANES study revealed what connection between sxs of metabolic syndrome
high BP correlated with high cholesterol and high cholesterol correlated with high BP
Expalin the concept of the "folate trap" that can lead to a folate deficiency
Methionine synthase uses 5-Me-THF from the folate pathway to regenerate methionine from homocysteine. This reaction takes Me-5-THF to THF which is returned to the folate pathway. A deficiency in B12 or methionine synthase can trap folate as 5-Me-THF and create a deficiency.
What are the major transport molecuels of ammonia to the liver
alanine, glutamine, serine
Explain how the SAM cycle is "reset" once SAM is converted to SAH after donation of a mtehyl group via a methyl transferase
SAH is hydrolyzed to adenosine and homocysteine. Homocystiene is converted back to methionine by adding a methyl group from 5-MeTHF, catalyzed by methionine synthase. This reaction also regenerates THF for the folate cycle.
Compare the lysosomal and ubiquitin proteasome protein degradation systems in terms of:
What reactions converte methionine into a good methyl group donor?
Methionine adenosyl transferase adds adenosine to methionine t ocreate SAM. The positive charge on the SAM molecule makes it 1000x more active than folate as a methyl group donor
In extrahepatic tissues, glutamine is a major transporter of ammonia. Explain how the glutamine is formed.(2 ways)
1. Ammonia is transfered onto a-KG from AAs via ALT, AST or other AT's to form glutamate. Glutamate is the converted into glutamine by glutamine synthetase
2. Free ammonia is added to a-KG by glutamate dehydrogenase. The Glutamate is then converted to glutamine by glutamine synthetase
What might cause a deficiency of SAM? How does this affect pregnancy?
SAM deficiency may be due to methionine synthase mutation, or a folate or B12 deficiency. Lack of SAM during pregnancy can lead t oneural tube defeccts.
Describe the remodeling that occurs with insulin resistance/ dyslipidemia
-too much VLDL, CETP messing things up
-TGs go to HDL and cholesterol goes to VLDL
-HDL gets degraded by hepatic lipase
-cholesterol rich VLDL and derivatives are proatherogenic
What happens if there is excess methionine not needed for the SAM cycle
It is degraded to succinyl CoA. The methionine goes through the first three steps of the SAM cycle to Homocysteine. Then it is converted to cystathionine by cystathionine B-synthase and then it is cleaved to cysteine and a-ketobutyrate. The a-KG goes through rxns of odd chain fatty acid metabolism to succinyl CoA
Alanine is a transport molecule used by muscle and kidney to carry ammonia to the liver. How is the alanine formed?
Free ammonia is added to a-KG by glutamate dehydrogenase to form glutamate. ALT then catalyzes the transfer of ammonia from glutamate to pyruvate forming alanine. Alanine transports carbon and ammonia to the liver.
What can cause high levels of homocystiene? What are high levels associated with
High levels of homocystiene can be caused by deficiency of folate, B12, methionine synthase , or PLP. It is associated with CVD, Alzheimer's disease, osteoporosis, and bone fractures.
which protein degradation system recognizes monoubiquitinated proteins
UP needs at least 4 ubiquitins
What is the cause of homocysteinuria? What is assoicated with it
Deficiency of cystathionine-B-synthase which normally condenses homocystiene and serine to form cystathionine.

Associated with mental retardation, thromboembolism, thin bones, osteoporosis, scoliosis, and lens dislocation
How does ammonia enter the liver to begin the urea cycle
1. Aminotransferases in the liver cytoplasm transfer ammonia from AAs to a-KG forming glutatmate which delivers the ammonia to the mitochondrion.
2. Free ammonia can enter the mitochondrion directly or be used for glutamine synthesis.
How is arginine synthesized?
From glutamate using the urea cycle reactions. The first half generates citrulline via nitric oxide synthesis. This occurs in the intestine. The second half occurs in the kidney where the citrulline is converted into arginine via argininosuccinate synthetase and argininosuccinate lyase.
how many carbons does cholesterol have? pregenolone
What AA is proline synthesize from
What three molecules enter the mitochondria for urea synthesis
glutamine, glutamate, free ammonia
How is nitric oxide formed
Formed from arginine via nitric oxide synthase, produces citrulline and NO. THB dependent reaction. Note problem for non-classical PKU patients
Explain how a protein is tagged and specified for ubiquiting protease system
1. Ub +ATP=> Ub-AMP
2.Ub-AMP=> Ub-E1
3. Ub-E1=>Ub-E2
4. Ub-E2 +E3+ Target=> Target-Ub
5.Target-Ub=> Target-Ub-Ub-Ub-Ub
Explain how glutathione is synthesized (which AAs are the precursors)
Made from glutamate, cysteine, and glycine using y-glutamyl cyseine synthetase and glutathione synthetase. An isopeptide bond is formed between glutamate and cysteine
The first step of urea synthesis is the relase of ammonia from glutamine and glutamate. How does this occur?
1. Ammonia is released from glutamate by glutamate dehydrogenase
2. Ammonia is released from glutamine by converting it to glutamate using glutaminase, then glutamate dehydrogenase releases the ammonia
How is GABA synthesized
from glutamate via glutamate decarboxylase, a PLP dependent enzyme
What Tx's can be used for insulin resistance/dyslipidemia
-diet, excercise, weight loss
-Statins-inhibt HMG CoA reductase (inhibit cholesterol synthesis)
-FIbrates-target PPAR-y to increase HDL
-resins/ bile acid sequestrants, excrete more LDL
How is histamine synthesized
from histidine via histidine decarboxylase, a PLP dependent enzyme
Glutamate dehydrogenase initiates the urea cycle by releasing ammonia from glutamate. How is this enzyme regulated
Allosteric control by the cellular energy level. Stimulated by high ADP, inhibited by high GTP
How is serotonin synthesized
Tryptophan=>5-hydroxytryptophan via tryptophan hydroxylase (THB)
5-hydroxytryptophan=> serotonin via aromatic AA decarboxylase (PLP)
How is the specificity of the ubiquitin proteases system determined
-recognition of E2's for specific E3's
-recognition of E3's for specific target proteins

(E3's recognize specific sequences such as cyclin destruction box, PEST, and the N-terminal amino acid)
How is melatonin synthesized
serotoni=>melatonin via methyl transferase (SAM)
What happens to the a-KG that is formed after glutamate dehydrogenase releases the ammonia from glutamate at the begining of urea synthesis
a-KG goes to the TCA cycle for conversion to OAA and synthesis of aspartate
How is dopamine synthesized
Tyrosine=>Dopa via tyrosine hydroxylase (THB)

Dopa=> dopamine via aromatic AA decarboxylase (PLP)
rank the lipoproteins in order of increasing density
How are norepinephrine and epinephrine synthesized
Dopamine=>Noreepinephrine via dopamine B-hydroxylase (ascorbate)

Norepi=>epi via phenylethanolamine N-methyltransferase (SAM)
What happens to the free ammonia that was released by glutamate dehydrogenase after initiation of the urea cycle?
The ammonia reacts with HCO3- to form carbamoyl phosphate. This is catalyzed by carbamoyl phosphate synthetase 1.
How are mleanins produced
Tyrosine=>dopqauinone=> melanins via tyrosinase
Describe the structure of teh proteasome
-4 rings, 2 alpha outer, 2 beta inner
-top and bottome alpha rings modify the protein for degradation and regulate
-central beta rings have proteases
Deficiency in tyrosinase leads to
Inability to synthesize melanins from tyrosine
Where does the carbamoyl phosphate synthetase 1 reaction occur? What co-factors are required
occurs in the matrix. Two ATP molecules are required for energy. N-acetylglutamate is an essential activator
Explain how the thyroid hormones are synthesized
Modification of tyrosine redicudes on thyroglobulin. Initiated by addition of iodine then oxidation, condensation, and cleavage.
What is the primary target tissue and effect of
glucocorticoids like cortisol, cortisone, corticosterone
Target= muscle and liver
Effect= protein catabolism, GNG, anti-inflammatory in high doses
What is the role of N-acetylglutamate in the urea cycle? How is it formed?
N-acetylglutamate is an essential activator for ccarbamoyl phosphate synthetase 1. It is synthetized from acetyl CoA and glutamate by acetylglutamate synthetase
Explain the role of the ubiquitin proteasome system in each of the following
-juvenile parkinson's
-HPV/cervical cancer
parkinsons-defective E3 can't recognize target proteins
HPV-viral E3 targets p53
Huntingtins= defective htt binds and inhibits proteasome
Which substrate "fuels" the urea cycle
carbamoyl phosphate
Which body shape is most at risk for development of metabolic syndrome
apple shape, central abdominal obesity
Where does the ornithine trascarbamoylase reaction occur?
in the matrix, contrast to the rest of the cycle reactions that occur in the cytosol
Describe how proteins are degraded in the stomach
-parietal cells release HCL, cheif cells release pepsinogen
-pepsinogen=>pepsin, cleaves proteins at peptide bond before large hydrophobic AAs
What happens to the carbamoyl phosphate that was formed during the carbamoyl phosphate synthetase 1 reaction. (What is the first step of the urea cycle)
Carbamoyl phosphate condensed with ornithine to form citrulline. The reaction is catalyzed by ornithine transcarbamoylase
What is the primary target tissue and effect of
mineralcorticoids like aldosterone, 11-dexoycorticosterone
Target=kidney tubules
Effect=sodium retention, Potassium excretion
Where does the argininosuccinate synthetase reaction occur
Describe how proteins are initially degraded in the intestine
Trypsinogen, chymotrypsinogen, and proelastase are secreted from the pancrease.Trypsinogen=> trypsin via enteropeptidase, trypsin activates other two enzymes
-act together to degraded proteins to free AAs and small peptides
What is the second step of the urea cycle (after the formation of citrulline)
Citrulline is transported from the matrix to the cytosol where is is converted to a citrullyl-AMP intermediate and then into argininosuccinate. This is catalyzed by argininosuccinate synthetase
in what form is cholesterol found in cell membranes
free, unesterified
Describe the argininosuccinate synthetase reaction. What is formed? What co-factors are invovlved
Citrulline is converted to argininosuccinate via a citrullyl-AMP intermediate. This reaction requreis ATP and Aspartate
Where do the following enzymes cleave
trypsin=after basic AAs
chymotrypsin= after cyclic aromatic AAs
elastase= after small AAs
What is the third step of the urea cycle (just formed argininosuccinate)
Argininosuccinate is cleaved into fumarate and arginine. This is catalyzed by argninosuccinate lyase. Note that this is a direct cleavage rxn that does NOT require water.
What is the primary target tissue and effect of
androgen -testosterone
Target-reproductive organs, muscle
Effect- Spermatogenesis, secondary male characteristics, bone maturation, virilization
What is the 4th step of the urea cycle (just formed arginine and fumarate)
Arginine is cleaved by arginase to form urea and ornithine. This enzyme requires a water moelcue.
Describe the euglycemic insulin clamp technique
used to measure insulin resistance, insulin is infused at a constant rate, glucose is infused at various rates until equilibrium is established. A slower rate indicates insulin resistance
What happens to the urea formed in the urea cycle
-most is transported from the liver via the blood to the kidney for excretion in the urine
-some diffuses into the intestine and is cleaved into CO2 and ammonia by bacterial ureas. Most of the ammonia is readsorbed but a small amount is excreted in the feces
Describe how proteins are degraded to completion in the intestine after the action of the endopeptidases (trypsin, chymotrypsin, elastase)
Carboxypeptidases and aminopeptidases (exopeptidases) cleave single AAs from the respective ends of the peptides
What is the net reaction of the urea cycle
NH4+ + HCO3- + 3 ATP + H2O+ Asparate=> Urea + 2 ADP + AMP +2Pi + PPi + fumarate
What is the primary target tissue and effect of
Estrogens like estradiol and estrone
Target-reproductive organs
Effect- feminization, cyclic rythms
How is the urea cycle regulated in both the short and long term?
When is the cycle unregulated?
short term-availability of N-acetylglutamate to activate carbamoyl phosphate synthetase I
long term-level of urea cycle enzymes
Note that the cycle is unregulated during starvation and in people on high protein diest
Explain how small peptides and free AAs are taken up from the intestine. Where do they go from there?
Taken up by class transporters and moved through the intestinal cell to the hepatic portal vein. Once at the liver, they are used to make new proteins or are distributed to other organs. Branched chain AAs (valine, leucine, isoleucine) are not degraded in the liver but rather used from energy in extrahepatic tissues
What happens to the fumarate that is generated in the urea cycle
Fumarate is converted to malate by cytosolic fumerase. Malate then crosses into the matrix and is used in the TCA cycle.
rank the lipoprotiens in order of decreasing diameter
How are the urea and TCA cycles linked by the aspartate-argininosuccinate shunt
OAA from the TCA cycle is used to synthesize asparate via AST which is needed for the argininosuccinate synthetase reaction
How does loss of amino acid transporter function present
SImilar to amino acid deficiencies
acidic=dicarboxylic aminoaciduria
basic= cystinuria, stones
neutral-neutral aminoaciduria, hartnup disease
aromatic= pellagra, the 4 D's
Which defiencies of the urea cycle are the most severe
Ornithine transcarbamoylase, carbamoyl phosphate synthetase argininosuccinate synthetase deficiencies are the most severe because the products synthesized are toxic and cannot be directly excreted in the urine.
What is the primary target tissue and effect of
target= uterus
effect= nidation, maintenance of pregnancy, cyclic rythyms
What are the results of a carbamoyl phosphate synthetase deficiency
Carbamoyl phosphate synthetase deficiency results in very high levels of ammonia because free ammonia cannot be efficiently metabolized. In addition, the urea cycle is inoperable because carbamoyl phosphate is not made to “fuel” the cycle.
How is the amminoia from amino acids metabolized
Removed from the AA and transfered to a-ketoacids to form amino acids that function as ammonia transport molecules to take the ammonia to the liver for urea synthesis
What are the results of an ornithine transcarbamoylase deficiency
Ornithine transcarbamoylase deficiency results in high levels of carbamoyl phosphate and free ammonia that cannot be detoxified by the urea cycle. Because of the high levels of carbamoyl phosphate in the mitochondria, a large portion will cross the mitochondria membranes and mix with the cytosolic pool of carbamoyl phosphate produced by carbamoyl phosphate synthetase II. Carbamoyl phosphate then is metabolized to orotate in the pyrimidine synthesis pathway. Excess orotate not needed to synthesize pyrimidines is excreted in the urine.
What did the pioglitazone in DAHL-S salt sensitve hypertensize rats show?
Using drugs to increase insulin sensitivity decreased blood pressure, demonstrated linked between insulin resistance and high bp
No detectabgle serum citrulline with excretion of orotate suggests a defiency of which enzyme of the urea cycle
ornithine transcarbamoylase
How is asparagine converted to an energy source (how does it enter a metabolic pathway)
Asparagine=>aspartate=> GNG or OAA to TCA
Why is dietary argnine give to treat argininosuccinate deficiency
-Argininosuccinate can be excreted into the urine so there is no concern of toxicity
-Arginine is give to fuel the urea cycle so that ornithine can be regenerated so that CP does not build up
What are the positive and negative effects of using synthetic androgens as anabolic steroids
positive-build muscle mass
negative-kidney, liver, heart problems
Benzoate and phenylacetate are used to Tx carbamoyl phosphate syntehtase, ornithien trasncarbamoylase, and argininosuccinate deficiencies. How do theses drugs work?
Reduce levels of ammonia by reacting with glycine and glutamine and forming hippurate and phneylacetylglutamine which can be excreted in the urine
How is apartate converted to an energy source (how does it enter a metabolic pathway)
Asparate=> GNG or => OAA for TCA
What is the genetic cause of ornithine transcarbamoylase deficiency
X linked
note that all other deficiencies of urea synthesis are autosomal recessive
descrbie phosphatidic acid, the basic unit of phospholipids
glycerol backbone with phosphate esterified to C3 instead of a fatty acids like in triglycerides
What general methods are used to treat deficiencies of the urea cycle system
1. liver transplant
2. waste product medications
3. low protein diet
How are cysteine, glycine, serine, and threonine (minor_ converted to an energy source (how do they enter a metabolic pathway)
Enter as pyruvate
where are the steroid hormones synthesized
adrenal cortex
How are isoleucine, lueicine, lysine, phenylalanine, tryptophan, and tyrosine converted to an energy source (how do they enter a metabolic pathway)
Enter as acetyl CoA
Describe the phenotype of insulin receptor knockout mice. What evidence did this provide concerning the cause of metabolic syndrom
Mice lacking the insulin receptor had hypertension, high TG, low HDL, and impaired endothelium dependent vasodilation
How are glutamine, arginine, proline, histidine, and glutamate converted to an energy source (how do they enter a metabolic pathway)
Glutamine, arginine, proline, and histidine are converted into glutamate which is converted into aKG and used in the TCA cycle
Describe the enzyme that converts cholesterol to prenenolone
-desmoalse a cytochrom P450
-localized to matrix side of inner mitochondrial membrane
-requires NADPH and O2
How are methionine, threonine, isoleucine, and valine (major) converted to an energy source (how do they enter a metabolic pathway)
Enter as succinyl-CoA
Chylomicrons are "enriched" in which substance?
Dietary triacylglycerides. The main role of chylomicrons is to bring dietary TGs from the intestine to peripheral tissues like muscle and adipose
How are tyrosine and phenylalanine converted to an energy source (how do they enter a metabolic pathway)
Enter the TCA cycle as fumarate and acetyl-CoA
What stimulates the conversion of cholesterol to pregnenolone
ACTH synthesized by the anterior pituitary acts on the adrenal cortex
What 4 products are AAs broken down into? What can they be used for?
1. pyruvate
2. acetyl-CoA
3. TCA cycle intermediates
4. one carbon units
Used for GNG, FA and ketone body synthesis, fuel for TCA, synthesis of other amino acids
Describe the association of insulin resistance with the determinates of arterial pressure
-increased HR
-decreased SV
-decreased CO
-increased PR
overall effect is increased arterial pressure
What is the first step of the phenylalanine degradation pathway?
Phenylalanine=> tyrosine
via phenylalanine hydroxylase
What is the net reaction of chytochrome P450's
What is the second step of the phenylalanine/ tyrosine degradation path (just formed tyrosine using phenylalanine hydroxylase)
Tyrosine=> p-hydroxyphenylpyruvate
via tyrosine aminotransferase
describe the structure of the cholesterol molecule
-27 carbons
-small polar head group, extensive non polar region with 4 fused rings
-low solublity in water, soluble when associated with lipoprotein
What is the third step of the tyrosine/ phenylalanine degradation pathway? (previous step:Tyrosine=> p-hydroxyphenylpyruvate via tyrosine aminotransferase)
p-hydroxyphenylpyruvate=> homogentisate
via p-phydroxyphenylpyruvate dioxygenase
Which electron carriers are involved in the mitochondrial steroid hormone synthesis
NADPH, adrenodoxin reductase, adrenodoxin, and cytochrome P450
What is the 4th step of the tyrosine/ phenylalanine degradation pathway?
(previous step: p-hydroxyphenylpyruvate=> homogentisate via p-phydroxyphenylpyruvate dioxygenase)
homogentisate=> maleylacetoacetate

via homogentisate 1,2 dioxygenase
The prothromobotic manifestations of metabolic syndrome include
-decreased plasminogen activator and increased activator inhibitor
-increased fibrinogen
-increased blood viscosity
What is the 5th step of the tyrosine/ phenylalanine degradation pathway?
(previous step:homogentisate=> maleylacetoacetate
via homogentisate 1,2 dioxygenase)
maleylacetoacetate=> fumarylacetoacetate
via maleylacetoacetate isomerase
Where are glucocorticoids (cortisol,cortisone, corticosterone) synthesized
Synthesis begins in the mitochondrial where cholesterol is converted to pregnenolone. Pregenenolone is then moved to the ER where is made into 11-deoxycortisol. 11-Deoxycortisol is taken back to the mitochondria where it is converted to cortisol and then exported
what is the 6th step of the tyrosine/ phenylalanine degradation pathway
(previous step: maleylacetoacetate=> fumarylacetoacetate
via maleylacetoacetate isomerase)
fumarylacetoacetate=>acetoacetate and fumarate

via fumarylacetoacetase
Where are chylomicrons assembled? Secreted?
Assembled in the intestine, secreted by enterocytes
what is the 7th step of the tyrosine/ phenylalanine degradation pathway
(previous step: fumarylacetoacetate=>acetoacetate and fumarate via fumarylacetoacetase)
acetoacetate=> acetoacetyl-CoA
via 3-keto-CoA transferase
Which electron carriers are used in microsomal (ER) steroid hormone synthesis
NADPH, cytochrome P450 reductase, cytochrome P450
Which enzyme deficiency causes classical PKU? How is the phenylalanine delt with and why is this bad
Deficiency in phenylalanine hydroxylase.
Instead of being converted to tyrosine, phenylalanine is convertedt phenylpyruvate via aminotransferase (uses pyruvate to alanine). Phenylpyruvate is converted to phenylacetate and phenyllactate which compete with transport of other amino acids that are required to make NTs, catecholamines, and proteins
In addition to the "deadly quartet" of sxs such as hypertension and dislipidemia, metabolic syndrome is associated with which disorders affecting "peripheral systems"
-obstructive sleep apnea
How is classical PKU treated
low phenylalanine diet, supplemental THB and AAs
where does the synthesis of mineralcorticoids (aldoesterone) occur?
final synthesis occurs in the mitochondrial, 11 hydroxylase, 18hydroxylase, and 18-ol-dehydrogenase are found in the mitochondria
What causes non-classical PKU
Deficiency in DHB reductase or other THB synthesis enzymes. Note that this disease causes much more severe problems than classical PKU because THB is required for lots of pathwyas
Where does the synthesis of phosphatidic acid occur
ER and outer mitochondrial membrane
How is non-classical PKU treated
PKU diet, supplemental THB, supplemental NT precursors
What is the key enzyme for directing steriods into the synthesis of glucocotricoids, androgens, and estrogens? Where is it found?
The key enzyme is 17 hydroxylase which takes pregenonolone to 17-OH-pregenolone and progesterone to 17-OH-progesterone. It is found on the endoplasmic reticulum in steroid secreting organs
What is the cause of tyrosinemia II (oculocutaneous)
deficiency in tyrosine aminotransferase which converts tyrosine to p-hydroxyphenylpyruvate.
Describe the changes in adiopokines/ inflammatory markers that are associated with metabolic syndrome
increase in: leptin, resistin, interluekins, TNF, C reative protein
decrease in-adiponectin (anti-atherogenic)
What are the sxs of tyrosinemia II?
How is it treated?
Accumulation of tyrosine in skin and eye
Tx with low tyrosine diet
Describe how steroid hormones are degraded
-no way to breakdown steroid ring
-partial catabolism and inactivation in liver reduces ketones and double bonds
-inactive metabolites are conjugated to glucuronic acid or sulfate and are excreted in the urine
What is the cause of tyrosinemia III? What are the sxs and Tx?
p-hydroxyphenylpyruvate dioxygenase deficiency. Benign because p-HPP can be excreted in the urine
After TGs are consumed, they are acted upon pancreatic lipase and broken down into FFA and MG. Describe how these products are then delivered to extrahepatic tissues.
Within the intestinal mucosal celll, the FFAs and MG are reassembled into TGs which are them packaged into chylomicrons. The chylomicrons then travel to tissues such as muscle and adipose where they are acted upon by lipoprotein lipase released FFA's again.
What is the cause of alkaptonuria
Homogentisae 1,2 dioxygenase deficiency (homogentisate=> maleylacetoacetate
What defect is the most common cause of CAH
21 hydroxylase which takes which takes progesterone to 11-deoxycorticosterone and 17-OH progesterone to 11-deoxycortisol
What are the sxs associated with alkaptonuria
-caused by homogentisate 1,2 dioxygenase deficiency
-dark urine because of excess homogentisate
-accumulation in joints and soft tissues=> arthritis and disc calcification
What are the criteria for Dx'ing metabolic syndrome
3 or more of:
central obesity
triglycerides >150
HDL <40 men, <50 women
hypertension >130/85
fasting glucose >110
What is the cause of tyrosinmeia I
fumarylacetoacetate deficiency
CAH often involves a deficiency of 21 hydroxylase preventing the synthesis of 11-deoxycorticosterone and 11- deoxycortisol from progesterone and 17-OH progesterone respectivley. What precursors accumulate as a result of this? What products are missing? Which sxs result?
-back up in pathway leads to excess progesterone and 17-OH progesterone
-the products are shunted to androgen synthesis leading to virilism
-cannot make aldosterone so salt wasting occurs
-need to administer glucocorticoids and aldosterone
What are the sxs associated with tyrosinemia 1
liver, kidney, spleen enlargement and destruction because fumarylacetoacetate is toxic
What is the source of carbon in cholesterol
acetyl CoA
Tyrosinemia type 1 can be treated using NTBC to induce tyrosinemia III. How does this help
NTBC inhibits p-hydroxyphenylpyruvate homogentisate which is the same enzyme inhibited in tyrosinemia III. The excess p-HPP can be excreted in the urine which diverts the degradation pathway and prevents build up of toxic fumarylacetoacetate
What is the cause of Addison's disease? How does this develop?
sxs and tx?
Cause=destruction of adrenal cortex via autoimmune or tuberculous adrenalitis
sxs=fatigue, weakness, weight loss, low BP, hyperpigmentation
Tx= replacement therapy with glucocorticoids and aldosterone
Which enzymes are each of the tyrosinemias associated with. Which is the worst?
In order of pathway
Type II= tyrosine aminotransferase
Type III= p-hydroxyphenylpyruvate dioxygenase= benign
Type I= fumarylacetoacetase= worst
How does the prevalence of metabolic syndrome vary with age
20-29 7%
60-69 44%
>70 42%
Explain the general scheme of branched chain AA degradation
AA=> a-keto acid via branched chain aminotransferase
a-keto acid=> Acyl CoA derivative via branched chain a-keto acid dehydrogenase complex
what are valine and isoleucine metabolized to
propionyl-CoA then succinyl-CoA
isoleucine is also degrasded to acetyl-CoA
What is the cause of Cushing's disease? sxs? Tx?
-excessive secretion of corticotropin by anterior pituitary tumors overstimulate the adrenal cortex leading to excess cortisol
-sxs= weight gain, muscle wasting, weakenss
-Tx= microadenomectomy, pituitary irradation, adrenalectomy
-note sxs mimic by chronic glucocorticoid therapy, stress, depression
what is leucine degraded to
acetoacetyl-CoA and acetyl CoA
Lipoprotein Lipase
-where is it expressed
-what does it's action depend on
-how does it's activity differ in varous tissues
LL is most present in adipose and muscle. IT is expressed on the endotheial surface of blood capillaries bound to heparan sulfate proteoglycans. IT's action requires apo CII.
Activity in adipose is induced by insulin, activty in the muslce remains high and is increased under catabolic conditions.
What is the cause of methylmalonyl acidemria
deficiency in methylmalonyl-CoA mutase or vitamin B12 deficiency, prevents the production of succinyl-CoA
Describe the mechanism of action of steroid hormone receptors
1. Hormone binds to receptor, induced confirmational change
2. Complex binds as a dimer to HRE in nucleus and recruits general transcription factors and coactivators to form active transcriptional complex
3. results in enchanced gene expression
what is the cause of maple syrup urine disease
branched chain a-keto acid dehydrogenase deficiency
The most important aspect of treatment for metabolic syndrome is
weight reduction (caloric restriction, therapy, activity, drugs, surgery)

**just at 10% reduction is beneficial!!
how is maple syrup urine diease treated
low protein diet, thiamin sup. aggressive management during acute metabolic decomposition
How does Tamoxifen treat extrogen receptor positive breast cancers (2/3 of breast cancers)
Tamoxifen is a synthetic anti-estrogen (SERMs) that functions as an antagonist in breast cancer cells. It binds to the steroid binding domain of the estrogen receptor and induces a confirmational change that prevents coactivators from binding thus preventing transcriptional activation
Describe the structure of phosphatidic acid, the common intermediate in the synthesis of phospholipids
-fatty acids from CoA derivatives are esterified onto the glycerol 3 phosphate background
-C1 is usally saturated
-C2 is usually unsaturated
Describe the structure of the DNA binding domain of steroid hormone receptors
Contain a zinc finger motiff which binds to the HRE sequence in the DNA
What are the dietary goals of Tx for meatbolic syndrome
-<7% of calories from saturted fat
-cholesterol <200mg/day
-limit trans fats
<6gm saltday
-restrict alcohol
What 4 domains must a steroid hormone receptor contain
1. activation
2. DNA bindng
3. hormone binding
4. nuclear localizaiton signal
Which apo protiens are expressed by chylomicrons? What do these proteins interact with
b-48 and A are original
Aquired from HDL:
CII-lipoprotein lipase
E-LDL receptor, hepatic lipase
How are the levels of steroid hormone receptors regulated in the short term compared to the long term
short term-directly via HREs, increase transcription within minutes
longer term- indirecty without the HRE, may take hours
What drugs can be used to Tx metabolic syndrome
-weight loss drugs (appetite/absportion)
-bile acid sequestrants
-fenogibrate to increase HDL (?)
which enzyme converts testosterone to DHT
Where does cholesterol synthesisi occur
How does the activity of DHT compare to that of testosterone. How does sensitivity to androgne vary amongst different tissues
DHT has a higher affininity for the androgen receptor
The prostate has 2x higher level of androgen receptor than skeletal muscle. This an important consideration for prostate cancer because most are androgen receptor dependent tumors
Describe the fate of chylomicron contents after initial lipolysis at the extrahepatic tissues
Residues TGs and the dietary cholesterol are now carried in the chylomicron remnant. The CR is taken up in the liver via the LDL receptor and heaptic lipase binding apo E. In the liver, the particles are endocytosed and catabolized
The majority of prostate cancers are androgen sensitive tumors and the prostate has a much higher levle of androgen receptors than other tumors. How does this concecpt relate to treatment of the cancer
Treatment is based on androgen deprivation.
Strategies include; castration (surgical or chemical), inhibtion of steroidogenic enzymes, anti-androgens, inhibtion of 5a-reductase
what are the sources of the glycerol 3 phosphate used in phospholipid synthesis
1. glycerol via ATP
2. DHAP via reduction
How doe the steroid hormone synthesis electron carriers differ in the mitochondria and ER
mitochondria-NADPH, adrenodoxin reductase, adrenodoxin

ER-NADPH, cytochrome P450 reductase
what are the three possible fates for the contents of chylomicron remnants
Contents=leftover TGs, dietary cholesterol
1. secrete into bile
2. change into bile acids
3. incorporate into nascent lipoproteins
Describe the steps leading to the formation of mevalonate
1. acetyl CoA x2=acetoacetyl CoA via thiolase
2. accetoacetyl CoA + acetyl CoA=HMG CoA via HMG CoA synthase
3. HMG CoA=>mevalonate via HMG CoA reductase
What are VLDL particples "enriched" in
rich it TGs
the role of VLDLs is to transport endogenous TGs from the liver to peripheral tissues
some cholesterol and cholesterol esters
What are the two methods by which an "x" group can be attached to phosphatidic acid
1. Attached an activated X group to the phosphate that's already there
2. Hydrolyze the phosphate and attach an X group that has a phosphate on it
Which apo proteins are expressed on VLDL? What do they interact with?
apoB-100=LDL receptor (low affinity)
apo CII-lipoprotein lipase
ApoE-LDL receptor (high affinity) heaptic lipase
What is the rate limiting step of cholesterol synthesisi
HMG CoA reductase
Where are VLDL particles assembled? Secreted?
assembled in the liver, secreted by hepatocytes.
what is a phosphatidate
a derivative of phosphatidic acid. Various X groups are attached to the phosphate of phosphatic acid including choline, ethanolamine, serine, glycerol, phosphatidylglyceron and inositiol
What is the overall purpose of VLDL particles
pathway for export from hepatocytes of excess endogenous TGs derived from lipgenesis, plasma FFA, and chylomicron remnants which would otherwise be stored in cdells
What does HMG CoA reductase require as a cofactor
NADPH (redox rxn, HMG CoA is a thioester, mevalonate is an alcohol)
Trace the metabolism of VLDL particles from out from and back to the liver
VLDL particles are packaged in the liver with TGs, cholesterol and cholesterol esters. The VLDLs leave the liver and are hydrolysed by liporportein lipase (activated by apo CII) and release FAs. The remnant, called IDL is removed fom the circuation by hepatocytes via the LDL receptor binding to apo E.
What are the long chain fatty acids usually associated with phosphatidylinositiol? Why is this significant?
C1= stearic acid
C2= arachidonic acid
imporant because phosphatidylinositiol is the main source of the arachidonic acid used to make ecosanoids
what is IDL enriched in
cholesterol esters because the TGs were delievered by VLDL to other tissues via lipoprotein lipase
What is the second stage of cholesterol synthesis after mevalonate has been formed
Conversion of mevalonate to activated isoprenes
which apo proteins are expressed by IDL?
B-100, C-II, E
what are the most abundant lipids in cell membranes
1. Phosphatidylcholine (lecithin)
2. phosphatidylethanolamine
3. phosphatidylserine
where does IDL come from? What happens to it?
VLDL becomes IDL after removal of TGs by lipoprotein lipase interacting with apo C. The IDL can be taken up by the liver via the apoE binding to the LDL receptor or converted into LDL.
To convert to LDL another apo C and the apo E lipoproteins are given back to HDL which converts the moleule to LDL which only expressed B-100
Describe how activated isoprenes are formed from mevalonate in the second stage of cholesterol synthesis
Two phosphate groups are added to the C5 OH group of mevalonate and one to the C3 OH group. A decarboxylation reaction then removes the C1 COO- group and the C3 phosphate group. The result is a 5 carbon activated isoprene e d3isopentenyl PP with C1=C2 which is in equilibrium with dimethylallyl PP with C2=C3
What is LDL enriched in
cholesterol esters
In one method of synthesizing phosphatidates from phosphatidic acic, the phosphatidic acid is activated and then reacts with the X group. Explain how this occurs
1. Phosphatidic acid reacts with CTP to make "activated' phosphatidic acid (CDP-diacylglycerol)
2. The CDP diacyglycerol attacks the X group and pyrophosphate is hydrolyzed
What apo proteins does LDL express
apoB-100, binds w/ low affinity to LDL receptor
Describe the formation of squalene, the third stage of cholesterol synthesis after the formation of activated isoprenes
1. The phosphate head of dimethylallyl pp condenses with d3isopentenyl PP forming a 10 carbon geranyl PP
2. a second d3isopentenyl PP condenses with geranyl PP to form a 15 carbon farnesyl PP
3. Two farnesyl PP's condense to form 1 30 carbon squalene
Where does LDL come from
derived from IDL follwoing removal of TG by hepatic lipase (via apoE)
In one method of synthesizing phosphatidates from phosphatidic acic, phosphate group is hydrolyzed off of phosphatidic acid and an X group attaches with its own phosphate. Explain how this occurs
1. The X group reacts with ATP to add one phosphate group
2. The X group then reacts with CTP to add an additional phosphate and create a high energy bond
3. The activated X group is attacked by the OH of the diacylglycerol (from phosphatidic acid)
4. THe CDP is released and the phosphatidate is formed
Which apo protien does hepatic lipase bind? which liporproteins express these apo's?
Hepatic lipase binds apo E
Apo E is expressed by Chylomicrons (aquired from HDL), VLDL, and IDL
What is the third step of cholesterol synthesis after the formation of activated isoprenes
Formation of squalene
Give two important roles of LDL
1. transport cholesterol to peripheral tissues
2. regulate de novo cholesterol synthesis at peripheral tissues
Describe the formation of phosphatidylserine
An exhange reaction in which serine attacks phosphatidylethanolamine and displaces the ethanolamine polar head group
LDL has no apo E, how does it bind the LDL receptor?
binds with low affinity (compared to IDL) via apoB-100
What is the final step of cholesterol synthesis after formation of squalene
Conversion of squalene to the four ring steriod nucleus (lanosterol) the transformation of lanosterol to cholesterol
Which apo proteins does HDL express? What do they bind to?
apoA-1-ABCA1, receives cholesterol, activates LCAT
apoC-II-binds lipoprotein lipase
ApoE-binds heaptic lipase and LDL receptor
Describe the structure of ether lipids
Instead of an acyl linkage, there is an ether linkage at the C1 carbon
Describe the formation of a mature, spherical HDL particle
1. originates in liver an small intestine
2. gains cholesterol via ABCA1 delivering to ApoA-1
3. Activated by ApoA-1, LCAT delivers cholesterol esters
Describe how squalene becomes lanosterol which contains the 4 rings characteristic of the steriod nucleus
1. squalene is activated by conversion to squalene epoxide
2. squalene epoxide is cyclized to lanosterol by oxidosqualene cyclase
How is HDL taken up by the liver and cells with active steroid hormone synthesis
scavenger receptor B1
Describe the synthesis of ether phospholipids
1. A fatty acyl group is added to the C1 carbon of DHAP
2. Because there is a carbonyl at C2 rather than an OH like in glycerol 3 phosphate, the fatty acyl group is relpalced by an alcohol which creates an ether linakge
3.After the ether linakge is made, the C2 carbonyl is reduced and a fatty acid via an acyl linkage is added
4. Once both of the fatty acid are added, the X group is attached
What is the general principle of reverse cholesterol transport
HDL promotes the efflux of cholesterol from macrophage foam cells in the aterial wall back to the liver
What general reactions must take place to convert lanoserol to cholesterol?
-3 demthylations
-reduction of a double bond
-migration of a double bond
what is the function of LCAT
-synthesis of cholesterol esters
-acts on HDL to esterify free cholesterol with a fatty acyl residue of lecithin
-the cholesterol esters are then trasfered via CETP from HDL to ther lipoproteins such as LDL and VLDL.
-this action works to remove cholesterol from HDL as cholesterol esters so that HDL can go pick up more cholesterol
How do phosphatidates and ether phospholipids differ in terms of starting material
Phosphatidates begin with glycerol-3-phosphate which has an OH group at C2. Ether phospholipids used DHAP which has a carbonyl at C2. This difference enables the alcohol replacement and formation of an ether linakge
WHat is the role of CETP
transfers cholesterol esters from HDL to LDL and VLDL

transfers TGs from other lipoproteins to HDL
Inherited disorders of cholesterol biosynthesis usually occur in which portion of the pathway
post-squalene portion
Explain how reverse cholesterol transport works
-LCAT transfers cholesterol esters to HDL
-SR-B1 removes cholesterol esters from HDL into hpeatic/steroidogenic cells
-This depletes HDL of cholesterol esters
-"empty" HDL goes back to the blood stream to extract mroe lipid
-in the liver, the cholesterol esters are hyrdrolyzed to cholesterol which is then excreted
What is unique about the structure of the ether phospholipid PAF? what consequence does this have
PAF contains just an acetyl residue at C2 instead of a long chain fatty acid. This make sthe molecule more water soluble which allows it to function in an aqueous environment. This is signficant because PAF is invovle dwith allergic and inflammatory responses including hypersensitivity and anaphylactic shock.
How is metabolic disease defined?
3 or more of the followingt
hypertriglyceridemia, low HDL, hypertension, increased waist circumfrence, elevated fasting glucose
All inherited disorders of cholesterol biosynthesis result in (2)
1. cholesterol deficiency
2. Developmental malformations (note tie to embryonic signaling pathways)
Explain how insulin resistsance leads to hypertriglycerideia in terms of VLDL metabolism
-free FFA levles increase
-excess lipids lead to stabilization of apo B, the major lipoprotein o fVLDL
-there is also lack of promotion of apoB degradation due lack of insulin response
-thus the combination of increased FFA and too much apoB leads to more HDL
Describe the structure of plasmalognes
Plasmalogens are ether phospholipids (ether linkage at C1) with an a,B unsaturated ether at C1
Plasmalogens can have various polar groups esterified to the C3 phosphate group
Insulin resistance leads to decreased lipoprotein lipase activty. What is the consequence of this in terms of VLDL metabolism
lipoprotein lipase is the major mediator of VLDL clearance. If it's activity is decreased, VDL and IDL increase.
Explain how HMG CoA reductase is regulated at the transcriptional level
The gene needs cleaved SREBP to bind to SRE in the DNA in order to activate transcription of HMG CoA reductase. SCAP senses the [cholesterol] and regulates release of SREBP. When cholesterol is high SCAP prohibits release of SREBP.. When cholesterol is low, SREBP undergoes a proteolytic clevage and is released to go on to the nucleus
How does insulin resistance change the activity of CETP
normally CETP transters colesterol esters from HDL to chylomicrons and VLDL in exchange for TGs. With insulin resistance alters this leading to cholesterol enriched VLDL/ LDL/ VLDL remants and triglyceride enriched HDL
Where does phospholipase A1 cleave?
Removes the fatty acid from C1, permits re-esterification with other fatty acyl CoAs
The altered action of CETP associated with insulin resistance leads to triglyceride enriched HDL. What is the consequence of this?
TG enriched HDL is a better substrate for hepatic lipase. The HDL is hydrolysed and it's circulating levels decrease
Explain how cholesterol synthesis is regulated by feedback inhibtion
metabolites of cholesterol stimulate proteolysis of HMG-CoA reductase protein
How does insulin resistance lead to hyperglycemia and ultimately B cell failure
-lack of insulin signaling decreases transport of insulin into peropheral tissues
-the elevated plasma glucose is sensed by the B cells which respond by producing more insulin
-continued stimulation of the B cells leads to hypertrophy, failure to secrete insulin normally, and ultimatley B cell failure
Where does phospholipase A2 cleave
Removes the fatty acid from C2, permits re-esterification with other fatty acyl CoAs
What are PPARs?
Ligand-activated transpription factors.
Once they are bound to their ligans, they form heterodimers with the nuclear receptor and modulate gene expression. PPARa and PPARg are targets for insulin resistance treatment
Explain how HMG-CoA reductase is regulated by phosphorylation
-phosphorylated HMG CoA reductase is inactive. This occurs in response to glucagon via AMPK
-dephosphorylation HMG CoA reductase is active. This occurs in response to insulin via HMG CoA reductase phosphatase
What is the target of fibrates? How do they work to treat the problems associated with insulin resistance?
Fibrates target PPARa which is a ligand activated transcription factor. The fibrates mimic the normal ligand (agonists) of PPARa and stimulate expression of beta oxidation genes. This decreates TGs and VLDL whine increases HDL synthesis and ApoA1 expression.
Where does phospholipase C cleave? What molecule is left?
Phospholipase C cleaves the O-P bond closest to the gycerol backbone, the result is diacylglycerol
What is the target of thiazolidinediones? How do they work to treat the problems associated with insulin resistance?
Thiazolidinediones target PPARgamma and function as agonisist. They lower glucose and enhance insulin sensitivity by upregulating the SRB1 receptor.
What would the phosphorylation state of HMG CoA reductase be in the fed state? Which regulatory enzyme would be active?
In the fed state, insulin will activate HMG CoA reductase phosphatase.
HMG CoA will be dephosphorylated and thus active
How is FH characterized clinically
1. elevated LDL
2. deposite of LDL derived cholesterol in the tendons and skin
3. inheritance as an autosomal dominant trait with gene dosage effect
Where does phospholipase D cleave? What molecule is left
Phospholipase D cleaves at the O-P bond cloest to the X group. The result is phosphatidic acid
The primary gene defect in FH is
a mutation in the gene encoding the LDL receptor
What would the phosphorylation state of HMG CoA reductase be in the fasting state? Which regulatory enzyme would be active?
in the fasting state, glucagon will activate AMPK which will phosphorylated and inactivate HMG CoA reductase
Whatchanges occur at the cellular level to respond to an oversupply oc cholesterol
1. inhibit HMG CoA reductase
2. activate ACAT (esterifies and stores cholesterol with the cell)
3. inhibit synthesis of LDL receptor
Describe the role of phospholipase C in cell signaling
Phospholipase C cleaves PIP2 into DAG and IP3 both of which trigger signaling events (IP3 triggers calcium release, DAG activates protein kinase C)
Describe how the LDL receptor gene is regulated
-regulated by SREBP membrane bound transcription factors
-when cholesterol is low, SCAP releases the SREBP which goes on to bind an SRE in the nuleus and express the LDL receptor
-when choleseterol is high, it binds to SCAP and prevents the release of SREBP
How do statins treat hypercholesterolemia
Statins are competitive inhibitors of HMG CoA reductase
(note pleiotropic action of increasing eNOS expression via modification of Rho thus improving endothelial fxn)
What is the "dual role" of the LDL receptor?
1. limit LDL production by enhancing the removal of IDL (the receptor bind to IDL with higher affinity than LDL)
2. Enhancec LDL degradation
Extracellular proteins can be attached to the outer surface of the plasma membrane by a GPI anchor. How does this work?
Glycosyl phosphatidylinositol (GPI) anchors are derivatives of phosphatidylinositol that contain an oligosaccahride attached to the carboxyl terminal of the protein via phosphatidylethanolamine.
How does a high dietary intake of saturated fats and cholesterol lead to elevated plasma LDL receptors.
The cholesterol in the diet binds to SCAP and prevents release of SREBP. This decreases the expression of heaptic LDL receptors which leads to increased plasma LDL.
How is cholesterol excreted
1. As free cholesterol in bile
2. Convertedto cholic acid and then excreted as bile acid
Describe 3 ways an FH heterozygote can be treated
a heterozygote has one heathly LDL receptor gene so therapies are aimed at increasing expression by inducing a cholesterol deficiency
1. Bile acid binding resins to increase excretion of cholesterol expression by the liver
2. HMG CoA reductase inhibitors to limit de novo synthesis
3. Diet low in cholesterol and fat
what are ecosanoids derived from
unesterified arachidonic acid (the precursor of which is linoleic acid)
Describe 3 ways an FH homozygote can be treated
Homozygotes have no normal receptor
1. LDL aphresis
2. liver transplantation
3. gene therapy
what are the three classes of ecosanoids? what is their common function
ecosanoids are paracrine hormones. They are divived into prostaglandins, thromboxanes, and leukotrienes
How is the arachidonic acid needed for ecosanoid synthesis obtained
Phospholipase A2 cleaves it from membrane phospholipids (phosphatidylinositol)
There are two different classes of enzymes invovled in ecosanoid synthesis. What are the enzymes and what do they make?
prostaglandin synthase=prostaglandins, prostacyclin, thromboxanes
What are the two fucntions of the prostagliandin synthase enzyme?
1. COX- cyclizes arachodonic acid
2.hyderoeroxidase-glutathione dependent reduction
Explain the synthesisi of prostaglandin H2 (the common precursor of prostaglandins and thromboxanes) from arachidonate
1. 2O2's are added to arachodonate via prostaglandin synthase COX activity. This cyclizes the ring and adds a peroxide formin prostaglandin G2
2. The peroxide is reduced to an alcohol via the hydroperoxidase activity of prostaglandin synthase forming prostaglandin H2
Prostaglandin H2 has 4 fates depending upon which enzyme acts on it. What are these enzymes and what do they result in?
1. prostacylin synthase=prostacycllin
2. PGH-PGE isomerase=prostaglandin E2
3. PGH-PGF 2a reductase=Prostaglandin F2
4. Thromboxane synthase= thromboxane A2
What is the function of porstacyclin
vasorelaxation and platele declumping, note that this is in opposition to thromboxanes
what is the function of prostaglandin E2
fever and pain
what is the function of thromboxanes
vasoconstriction and platlet aggregation, note that this is in opposition to prostacylins
how are the prostaglandins distinguished from other ecosanoids
The action of the COX enzyme using 2 O2's cyclizes C8-C12 of arachidonic acid to form a characteristic 5 membered ring
Describe the structure of thromboxanes
The cyclopentane ring of PGH2 is converted into a six membered oxygen-containing ring
How are corticosteroids anti-inflammatory
they inhibit phosholipase A2 and reduce the rate of arachidonic acid production. This in turn decreases prostaglandin/ thromboxane synthesis because arachidonic acid is the precursor
How are NSAIDs like aspirin anti-inflammatory
They block prostaglandin synthesis from arachidonic acid by inhibiting the COX activity of PGS. Aspirin covalently acetylates COX and blocks the active site. Blocking this step leads to the wide ranging effect of aspirin on inflammation, fever, pain, and blood clotting
Lipoxygenase and COX both act on arachidonic acid to carry out ecosanoid synthesis. How do they differ in their actions
COX adds 2 O2 to form PGG2 leading to the synthesis of prostaglandins and thromboxanes, Lipoxygenase adds 1 O2 to from HPETE leading to the synthesis of leukotrienes
What is the common structural feature among all leukotrienes
four double bonds
Outline the synthesis of leukotriene A4 from arachidonic acid (A4 is the branch point for several other leukotrienes)
1. 5-LO adds 1 O2 to arachidonic acid to produce HPETE
2. A synthase generates an epoxide forming Leukotriene A4
Describe the formation of leukotriene B4 fom A4
a synthase adds water to the double bond between C11-C12, (gets rid of the epoxide)
Describe the formatio of the series of leukotrienes C, D, and E from A4
Reduced gluthathione opens up the epoxide ring of A4 to create C4, a dipeptidase removes glutamic acid to make D4 and then glycine to make E4
what are lipoxins
products of mutiple lipoxygenase pathways characterized by hydroxyl groups attached to C5 and C6
Describe the opposing functions of leukotrienes and lipoxins
leukotrienes= pro-inflamatory
lipoxins= anti inflmamatory
How do drugs like singulair and zafirlukast help asthma
block the binding of leukotrienes to lung smooth muscle
What is the physiological role of LTC4, LTD4, and LTE4
slow reacting substances of anaphylaxis
what is the physiological role of LTB4
chemotatic agent that brings neutrophils to sits of infection
describe the general structure of sphingolipids
Sphingosine backbone with C2 AMIDE linked fatty acids and C3 polar group
Describe the basic structure and function of sphingomyelines
-contain phosphocholine or phosphoehtanolamine as their polar group
-abundant in myelin
Describe the basic structure an function of glycosphingolipids
-polar groups with one or more sugars
-occur on the outer sufaceds of the plasma membrane, uncharged at pH 7 (contrast to gangliosides)
Describe the basic structure and function of gangliosides
-polar groups comprised of oligosaccharides with one or more NANA's at the termini, ngative charge at pH 7 (contrast to glycosphingolipids)
-found in nervous system esp. grey matter, bind cholera toxin
Describe the systhesis of sphingosine
Palmitoyl CoA and serine condense, are reduced, and a double bond is added. The initial condensation is catalyzed by palmitoyltransferase and is driven by the clevage of the thioester bond and release of CO2. Reduction occurs via NADPH and the double bond is introduced via FAD. Serine contrubes C1,C2, and the amino group, palmitic acid provides the remaining carbons
What is a cermaide
the basic unit of sphingolipids, the amino group of sphingosine is acylated by reacting with a long chain fatty acyl CoA
How are gangliosides formed?
step by step addition of sugar residues to ceramide via activated sugars.Gangliosides begin with cerebrodies and proceed through globosies until a sialic acid residue is attahced.
Describe the degradation of sphingolipids
-occurs in the lysozome
-results in shpingosine and fatty acids
-sphingolipidoses result if there is a defect in the pathway
What is the cause of Tay-Sach's disease?
-deficiency in B-hexosaminidase A which blocks the degradation of gangliosides
-manifests in the brain, neurons swell with lipid filled lysosomes
-motor weakness, demented, death before 3
-early oneset due to high ganglioside turnover in neonates
what is the cause of Niemann-pick iease? Features?
-deficiency in sphingomyelinase preventing degradation of sphingomylein into ceramide and phosphocholine
-mental retardation, hepatosplenomagdaly due to lipid deposits
-death in early childhood
What are polyisoprenoids derived from
5-carbon isoprene units
What is the characteristic structure of seroids
4 rings, synthesized from squalene