Unit 6 Diseases Flashcards
Von Gierke Disease (Type I) Defective Enzyme: Organ affected: Glycogen in the affected organ: Clinical features:
Von Gierke Disease
Defective Enzyme: glucose-6-phosphatase (or transport system)
Organ affected: Liver & kidney
Glycogen in the affected organ: Increased amountl normal structure
Clinical features: massive enlargement of liver, failure to thrive, severe hypoglycemia, ketosis, hyperuricemia, hyperlipemia
Anderson Disease (Type IV) Defective Enzyme: Organ affected: Glycogen in the affected organ: Clinical features:
Anderson Disease
Defective Enzyme: branching enzyme (a1-4 to a1-6)
Organ affected: Liver and spleen
Glycogen in the affected organ: normal amount, very long outer branches
Clinical features: progressive cirrhosis of the liver. Liver failure causes death, usually before age 2
McArdle Disease (Type V) Defective Enzyme: Organ affected: Glycogen in the affected organ: Clinical features:
McArdle Disease
Defective Enzyme: Phosphorylase
Organ affected: Muscle
Glycogen in the affected organ: Moderately increased amount, normal structure
Clinical features: Limited ability to perform strenuous exercise b/c of painful muscle cramps. Otherwise, pt is normal & well-developed
What happens when there’s a deficiency in Fructose-1-phosphate aldolase?
F-1-P aldolase is the only enzyme that will get fructose into the glycoysis cycle by doing aldol cleavage of F-1-P into glyceraldehyde and DHAP, which will then be converted in Glyceraldehyde phosphate & into glycosis. Hence, deficiency will lead to liver damage and hypoglycemia.
What happens when there’s a deficiency in galactose kinase?
Galactose kinase will phosphorylate galactose into galactose-1-phosphate which will be worked on by other enzymes to get it into glycolysis. Deficiency will cause formation of galacitol, which causes cataracts. Pt should remove lactose from diet.
What happens when there’s a UMP transferase deficiency?
UMP transferase aka galactose-1-phosphate uridylyl transferase catalyzes galactose-1-phosphate to form glucose-1-phosphate which phosphoglucomutase can change into glucose-6-phosphate and into glycolysis. Def in UMP transferase will lead to mental retardation and liver failure. Treatment includes newborn screening and removal of lactose from diet.
Where is the site of action of arsenite poisoning?
arsenite will irreversibly chelate with dihydrolipoamide, which is an impt prosthetic group of one of the 3 enzymes (dihydrolipoyl transacetylase) in the pyruvate dehydrogenase complex which is the complex responsbile for making pyruvate into acetyl coA. Without this, then the person can’t survive b/c won’t be able to do aerobic respiration.
NADPH is used in biosynthesis and detoxification. Cytochrome P450 uses NADPH in the small intestines to detoxify what?
xenobiotics (poisons, toxins)
What is the role of NADPH in red blood cells?
needed to detoxify reactive oxygen species
Over 400 million people have glucose-6-phosphate dehydrogenase (G6PDH) deficiency. It is the most common enzyme deficiency. What are the consequences?
G6PDH is the first enzyme in the pentose phosphate pathway which will catalyze the rxn from G-6-P to 6-phosphoglucono-delta-lactone, producing an NADPH. This enzyme deficiency will result in deficient levels of NADPH which is bad b/c NADPH is impt for detoxification of ROS, toxins, etc. They will have hemolytic anemia when they ingest fava beans (favism).
What is the evolutionary advantage of G6PDH deficiency?
it’s better to pay the metabolic cost of a faster rate of turnover of RBC’s than to die from malaria.
Explain the concept of “oxygen debt” in regards to the liver and its role in the cori cycle.
The cori cycle involves the production of lactate in muscle that needs more ATP. The lactate will be carried to the liver where it is converted to glucose (gluconeogenesis, using 1 ATP + 1 GTP). The glucose is released back into bloodstream. After exercise, this continues as muscle glycogen stores are replenished. The amount of O2 consumed in liver during this rebuilding process of muscle glycogen is called the “oxygen debt”
What is going on when you crack open an egg that’s been in the fridge for way too long?
We can smell H2S which is due to acidification of the tissues producing H2S gas due to iron sulfur proteins
Translocase (ADP/ATP, and Pi translocases) inhibitors inhibit oxidative phosphorylation. What do atractyloside and bongkrekic acid inhibit?
They inhibit ADP/ATP transport. Atractyloside prevents binding of ADP while bongkrekic acid prevents release of ADP. Both result in convulsions of a hypoglycemia nature, collapse and death.
-ADP/ATP translocase takes one ADP in and one ATP out, effectively removing one negative charge from the mitochondrial matrix (electrogenic)
Translocase (ADP/ATP, and Pi translocases) inhibitors inhibit oxidative phosphorylation. What do mercurous salts inhibit?
Inhibit Pi transport by rxn with essential -SH, leading to muscle spasms, depression, death from kidney failure usu w/in a week of exposure.
-Pi translocase moves 1 H+ and Pi- into the cell (electroneutral)
What is 2,4-dinitrophenol?
It is a uncoupler, which means it discharges the pH gradient, using O2 without the presence of ADP. People present with profuse sweating, collapse, death. Formerly used for weight reduction.
What is oligomycin?
A phosphorylation inhibitor, which prevents use of the electrochemical gradient to drive ATP synthesis by blocking Fo. It is fatal.
What is rotenone?
It is an etc inhibitor, inhibiting at 1st coupling site, causing nausea, vomiting, convulsions and death from respiratory paralysis.
What is amytal?
It is a barbiturate that inhibits chain ETC at 1st coupling site. Overdose causes the same symptoms as rotenone: nausea, vomiting, convulsions and death from respiratory paralysis.
What does cyanide do to the ETC? How to treat it?
Inhibits chain at cytochrome a3, blocking O2 binding by taking its place by binding to FeIII. It results in convulsions, unconsciousness, death from respiratory paralysis. An antidote is nitrite & thiosulfate IV and administer O2.
What is antimycin A?
It is an ETC inhibitor that inhibits chain at 2nd coupling site. It’s fatal.
How does CO interrupt the ETC?
It inhibits chain at cytochrome a3, blocking O2 binding by binding to FeII. Death results from interaction w/ Hb before it can reach the respiratory chain. Dizziness, vomiting, increase then decrease pulse and respiration, collapse and death. Treatment is O2 administration.
What are 3 causes of steatorrhea (excessively fatty stools)?
1 - failure of bile production or blockage of bile flow
2 - exocrine pancreas dysfunction or obstruction of pancreatic duct
3 - failure of uptake into intestinal mucosal cells (enterocytes)
Hartnups disease
Background: there are 5 transporters located on intestinal epithelium that help in amino acid absorptions (either Na+ or H+ symporters)
Hartnup’s disease is caused by a deficiency in the transport of neutral & aromatic acids (e.g. phenylalanine, tryptophan). Therefore, more of these a.a. will be detected in urine
Symptoms: pellagra-like (dermatitis, diarrhea, dementia, death) b/c tryptophan is needed to build niacin & niacin deficency causes pellegra
Treatment: niacin
Cystinuria
Background: there are 5 transporters located on intestinal epithelium that help in amino acid absorptions (either Na+ or H+ symporters)
Cystinuria is caused by a defect in the transporter responsible for transporting basic a.as and cystine
Symptoms: cystine accumulations will lead to kidney stones
Treatment: penicillamine
Cystic Fibrosis is an AR disease that manifests with pulmonary and digestive issues. Explain the reason for the digestive issues.
There’s a defect in the chloride channels in the pancreatic secretory ducts. They harden and eventually block, leading to a lack of pancreatic enzymes in the intestinal lumen. These patients will not be able to digest proteins. They must be given oral supplements of pancreatic enzymes
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
Which is the most common enzyme deficiency in the urea cycle? In this urea cycle disorder, what is found high in blood and urine?
OTC deficiency (OTC catalyzes the rxn from ornithine to citrulline in the mitochondria) is called Hyperornithinemia. Patient will have high levels of NH4, orotate and ornithine in blood, and high levels of ornithine in urine. They will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
Which enzyme defect causes arginiosuccinic aciduria? what is found high in blood and urine?
Argininosuccinase deficiency (argininosuccinase breaks down argininosuccinate into arginine & fumarate) will lead to high levels of NH4 and argininosuccinic acid in blood, and high levels of arginosuccinic acid in urine. Affected individuals will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
What enzyme defect causes hyperammoniemia? what is found high in blood and urine?
Carbamoyl phosphate synthase deficency (the 1st step of the urea cycle converting NH4+ CO2 + 2ATP into carbamoyl phosphate) will result in high levels of NH4 in in blood, nothing detectable in urine. Affected individuals will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
What enzyme defect causes arginiemia? what is found high in blood and urine?
Arginase deficiency (arginase will break down arginine into urea + ornithine) will lead to high levels of NH4 and arginine in blood, and high levels of arginine, lysine, and ornithine in urine. Affected individuals will have normal intelligence.
Genetic defects in enzymes of the urea cycle can lead to high serum levels of ammonia, which is toxic and can cause brain damage. Symptoms usually start in infants & include convulsions and ataxia.
Of the 5 urea cycle disorders we learn, which is the only one that causes mental retardation? what is found high in blood and urine?
Citrullinemia will cause mental retardation. It is due to a argininosuccinate synthetase deficiency. Argininosuccinate synthetase synthesizes argininosuccinate from citrulline + aspartate + ATP. There will be high levels of NH4 and citrulline in blood, and high levels of citrulline in urine.
Maple Syrup Urine Disease
Problem in the pathway of degrading branched amino acids (valine, isoleucine, and leucine), especially in the branched chain alpha-keto acid dehydrogenase enzyme. Patient’s urine will smell like maple syrup and will have seizures and other symtpoms. Treatment includes dietary restriction of valine, isoleucine and leucine. Some patients respond to high doses of thiamine (vit B1)
Phenylketonuria (PKU) vs Atypical PKU vs Maternal PKU
PKU - genetic defect in phenylalanine hydroxylase causing build up of phenylalanine, which can be converted into phenylpyruvate (bad!), leading to severe mental retardation. Dietary restriction of phenylalanine until 16 is advised to prevent mental retardation. In these patients, tyrosine becomes essential.
Atypical PKU -genetic defect is in BH2 (tetrahydrobiopterin) reductase, responsible for making BH4, which is a cofactor of phenylalanine hydroxylase. No treatment.
Maternal PKU -mothers with PKU should avoid phenylalanine b/c too much phenylalanine is bad for the fetus.
Homocystinuria
A defect in an enzyme called cystathionine synthase (homocysteine synthesis from methionine + serine). Patient presents with increased risk of atherosclerosis. Some die early of heart disease. There are mental disabilities as well. Giving patient Vit B6 (PLP) supplement can help (it’s a cofactor for the enzyme).
Cystathionuria
A defect in enzyme cystathionase part of the pathway in making cysteine from serine and methionine. Symptoms are increase risk of heart disease. Can be treated with Vit B6.
Alkaptonuria
Defect in homogentisate oxidate (part of pathway of converting phenylalanine into acetoacetyl CoA) leading to dark urine and arthritis.
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Tay Sachs Disease.
- deficiency in b-hexosaminidase A or activator protein in some cases
- accumulation of gangliosides
rapid, progressive & fatal neurodegeneration, muscular weakness, seizures.
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Gaucher Disease (MOST COMMON).
- deficiency in B-glucosidase (glucocerebrosidase)
- accumulation of glucocerebrosides
hepatosplenomegaly, osteoporosis in long bones, CNS involvement in infantile & juvenile forms
Treated with enzyme replacement therapy
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Metachromatic Leukodystrophy
- deficiency in arylsulfatase A & some times in activator protein
- accumulation of sulfatides
cognitive deterioration, demyelination, progressive paralysis & dementia in infantile form,
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Krabbe disease (Globoid cell leukodystrophy)
- deficiency in b-galactosidase (galactocerebrosidase)
- accumulation of galactocerebrosides
mental & motor deterioration, blindness & deaf, near-total loss of myelin, globoid bodies in white matter of brain
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Gm1 Gangliosidosis.
- deficiency in B-galactosidase
- accumulation of gangliosides & keratin sulfate
neurologic deterioration, hepatosplenomegaly, skeletal deformities, cherry-red macula in infantile form.
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Sandhoff disease
- deficiency in B-hexosaminidase A & B
- accumulation of Gm2 and globosides
neurologic symtpoms
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Fabry Disease (only X-linked one; all the rest are AR)
- deficiency in a-galactosidase
- accumulation of globosides
red-purple skin rash, kidney & heart failure, burning pain in lower extremities. Enzyme replacement therapy can help.
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Niemann-Pick Disease (A+B)
- deficiency in sphingomyelinase
- accumulation of sphingomyelin
hepatosplenomegaly, neurodegenerative course (type A), cherry-red macula
Defect in degradation of sphingolipids can cause lysosomal storage disorders/sphingolipidoses b/c degradation occurs in lysosomes.
Explain which enzyme is deficient and which substrate is accumulated in Farber Disease
- deficiency in ceraminidase (last step of degradation)
- accumulation of ceramide
painful & progressive joint deformity, subcutaneous nodules of lipid-laden cells, hoarse cry, tissues show granuloma.
List the essential amino acids
Phenylalanine Valine Threonine Tryptophan Isoleucine Methionine Histidine Arginine (during growth) Leucine Lysine
List the essential fatty acids
Linoleic (18:2, omega 6)
Linolenic (18:3, omega 3)
Parkinson’s disease
dopamine secretions are lowered due to problems with basal ganglia. Treat with L-DOPA
What are MAO inhibitors used for?
MAO inhibitors increase levels of catechols by inhibiting monoamine oxidase, which breaks catechols down. They act as anti-depressants.
Albinism
defect in melanin (precursor a.a. = tyrosine) synthesis causing lack of pigmentation.
Sulfa drugs work by mimicking?
Bacteria make their own folate (folate is essential in humans). Sulfa drugs inhibit folate biosynthesis by mimicking p-aminobenzoic acid, which is one of 3 structural components of folate.
THF is a 1-C carrier in which the carbon fragment is bonded to either N5, N10 or both in 3 different oxidation states. There is a non-reversible conversion from N5,N10-methylene-THF, using FADH2 to generate N5-methyl THF. Defect in this enzyme that generates N5-methyl-THF causes an increase risk of, and a decrease risk of?
Increase risk of heart disease and a decrease risk of colon cancer.
What are some drugs that can cause folate deficiency?
- oral contraceptives
- barbiturates
- methotrexate & amnopterin = “anti-folate” because they inhibit dihydrofolate reductase.
Dihydrofolate reductase catalyzes THF synthesis:
folic acid –> dihydrofolic acid –> THF, using 2 NADPH.
Folate deficiency during pregnancy
- can lead to neural tube defects
- impt to take folate supplements b/c fetus demands more folate intake
Methotrexate and amnopterin are anti-cancer drugs that are anti-folate. Which enzyme do they inhibit?
they inhibit dihydrofolate reductase.
Dihydrofolate reductase catalyzes THF synthesis:
folic acid –> dihydrofolic acid –> THF, using 2 NADPH.
Vitamin B12 (cobalamin) deficiency
pernicious anemia
demyelination & degeneration of spinal cord
Vitamin B12 deficiency due to problems with production of intrinsic factor
elderly tend to secrete less intrinsic factors. People who have vit. B12 deficiency due to instrinsic factor problem will need Vit. B12 injections.
Methylmalonic aciduria
AR disorder in Vitamin B12 metabolism, affecting conversion of L-methylmalonyl CoA to succinyl CoA, leading to increase levels of methylmalonic acid which is fatal if untreated.
What is the folate trap?
- occurs when B12 is deficient
- Vitamin B12 is a cofactor of homocysteine methyl transferase (homocysteine –> methionine), which is the only rxn in our body that gets rid of N5-methyl-THF into THF. If there’s no Vit B12, then we cannot use the build-up of N5-methyl-THF into making THF, leading to a folate deficiency = ANEMIA
-B12 deficiency + folate supplementation –> neurological problems w/o anemia
Cholesterol influx = dietary cholesterol, synthesis in liver and extrahepatic tissues
Cholesterol efflux = secretion into bile, secretion of VLDL, and conversion to bile acids/salts
If this balance is disturbed, what will happen?
deposition of cholesterol in endothelial linings of blood vessels.
Sitosterolemia
-excess cholesterol & b-sitosterol (a plant sterol) upon entering enterocytes are actively transported back into intestinal lumen by ABC family of transporters (ABCG5 or ABCG8)
Rare AR defect in either ABCG5 or ABCG8 transporters. Accumulation of b-sitosterol cholesterol in enterocytes eventually enter blood stream increasing risk of cardiovascular morbidity.
What does the drug ezetimibe do?
It blocks cholesterol intestinal absorption thru enterocyte brush border.
Smith-Lemli-Opitz Syndrome (SLOS)
- AR d/o of cholesterol biosynthesis
- defect in 7-hydroxycholesterol-7-reductase (the last step in making cholesterol)
Statin drugs
are structural analogs of HMG = competitive inhibitors of HMG CoA reductase to lower plasma cholesterol levels
Cholethiasis/cholesterol gallstone disease
movement of cholesterol into the bile must be accompanied by bile salts and phospholipid secretion. if there’s increased cholesterol secretion and is not balanced by bile salt and phospholipid secretion, this will cause precipitation of cholesterol & formation of gallstones.
ApoE2 variant puts a person in increase risk for?
Type III hyperlipidemia/Dysbetalipoproteinemia
-increase chylomicrons & VLDLs in plasma b/c ApoE2 binds poorly to receptors
-hypercholesterolemia & premature atherosclerosis
ApoE4 variant puts a person in increase risk for?
Alzheimer’s Disease
Nonalcoholic fatty liver (hepatic steatosis) occurs when what balance is screwed up?
an imbalance between TAG synthesis and secretion of VLDL
Deficiency in LPL or ApoCII leads to?
Type I hyperlipoproteinemia/familial LPL deficiency leading to accumulation of chylomicron TAG in plasma. Ppl will have increase risk for pancreatitis.
LDLR deficiency
Type II hyperlipidemia (familial hypercholesterolemia) increases plasma LDL-cholesterol due to point mutations in LDLR gene (mainly deletions), not only limited to ligand binding domain, but also in EGF precursor homology, O-linked sugars, membrane spanning, cytoplasmic, signal sequence domains.
Tangier’s disease
rare deficiency in ABCA1 transporter which is responsible for transferring cholesterol into peripheral tissues. Defect in transporter will lead to absence of HDL particles b/c of degradation of lipid free ApoA1.
Reverse cholesterol transport is in part the reason for what relationship?
-inverse relationship btw plasma HDL and atherosclerosis, explaining the role of HDL as the “good cholesterol carrier.”
Explain the 5 steps of plaque formation
1 - when there’s endothelial injury (caused by oxidized/modified LDL), monocytes adhere to endothelial cells, move to subendothelium & are converted into macrophages
2 - macrophages consume excess oxidized LDL forming foam cells
3 - foam cells accumulate, release growth factors and recruit smooth muscle cells that will secrete collagen and take up lipids and make more foam cells.
4 - low-affinity, non-specific & non-regulated scavenger receptors (SR-A) take up modified LDL
5 - high affinity receptors specific for LDL are downregulated when cell has sufficient cholesterol
3-b-hydroxysteroid dehydrogenase deficiency
This enzyme is responsible for making progesterone from pregnenolone. Progesterone is the precursor to the mineralocorticoids, glucocorticoids and sex hormones. Defect in this enzyme will lead to NO mineralocorticoids, glucocorticoids and androgens. They will have female-like genitalia and will have salt excretion in urine.
17-a-hydroxylase deficiency
This enzyme is responsible for converting progesterone into 17-a-hydroxyprogesterone. 17-a-hydroxyprogesterone can either make cortisol or androgens. Therefore, this enzyme deficiency will result in no glucocorticoids and androgens and increase mineralcorticoids leading to HTN. Ppl will also have female-like genitalia.
21-a-hydroxylase deficiency
This enzyme directs progesterone into the aldosterone synthesis path and 17-a-hydroxyprogesterone into the cortisol pathway. This defect will lead to no mineralcorticoids and glucocorticoids, and increase amts of androgens. ppl wil have increase masculinization and virility.
11-b-hydroxylase deficiency
This enzyme is responsible for 11-deoxycorticosterone –> corticosterone (aldosterone synthesis) and for 11-deoxycortisol –> cortisol. Defect will lead to decrease cortisol, aldosterone and corticosterone. There will be increase 11-deoxycorticosterone = fluid retention; and increase androgens = masculinization and virilization.
Defects in enzymes in steroid hormone synthesis from cholesterol belong to a class of disorders known as
Congenital adrenal hyperplasias
ACE inhibitors
treat renin-dependent HTN
Aromatase inhibitors used in?
hormone positive (estrogen responsive) breast cancer in post-menopausal women
Rickets
Vit D deficiency in children, leading to formation of collagen matrix but insufficient mineralization = soft and pliable bones
Osteomalacia
Vit D deficiency in adults, leading to demineralization of existing bones = more susceptible to fractures
Renal Osteodystrophy
chronic kidney disease causes decrease synthesis of active vit D & increase retention of phosphate = hypocalcemia & hyperphosphatemia
hypocalcemia will lead to increase PTH and associated demineralization
Hyperthyroidism’s effect on calcium and phosphate levels
lack of PTH leading to hypocalcemia and hyperphosphatemia
Vitamin D toxicity is characterized by what symptoms?
loss if appetite, nausea, thirst and stupor
-enhanced Ca2+ absorption & bone resorption leading to hypercalcemia. The Ca2+ will deposit in many organs, particularly in arteries and kidneys.
Which vitamin D is the major form of Vitamin D in the plasma?
25-hydroxycholecalciferol (25-OH-D3 or calcidiol) is what is being measured in serum
A patient with elevated serums of a-amylase most likely has which disease?
pancreatitis b/c a-amylase is easy to measure in labs and often used to detect pancreatitis. And the pancreas secretes a-amylase.
Glucose is the only fuel that can be used by all human cell types. It is the exclusive fuel of which cell? And the major fuel of which organ?
It is the exclusive fuel of RBCs and the major fuel of the brain.
Which organ plays a special role in carb metabolism in that it is responsible for supplying glucose to other tissues via bloodstream (gluconeogenesis and glycogenolysis)?
The liver
natural uncouplers aka uncoupler proteins
- in mitochondria of brown adipose tissue
- involved in non-shivering thermogenesis & weight loss
- a pore that lets H+ leak into mitochondrial matrix disrupting the H+ gradient w/o making ATP.
- works via activating g-protein coupled receptors –> cAMP –> PKA
Natural phosphorylation inhibitor aka the inhibitor protein
- “emergency” kind of protein
- protects against rapid ATP hydrolysis during ischemia
- abundant in heart
- normally it does not bind F1 of ATP synthase, but in ischemia, pH of matrix space decreases (more H+), protonating inhibitor protein causing conformational change leading it to bind F1
- binds F1 to prevent H+ gradient to be used for ATP during ischemia
- once O2 is reintroduced, inhibitor protein is deprotonated = inactive
Azaserine
-analog of glutamine that inhibits rxns that glutamine is used in, such as GMP synthase, CPSII, CTP synthase, PRPP aminotransferase, asparagine synthase.
5-fluorouracil
- is a suicide inhibitor that inhibits formation of dTMP
- in cells, converts 5’-monophosphate into F-UMP
- F-UMP is phosphorylated to F-UDP then reduced to F-dUDP then to F-dUMP
- F-dUMP has anti-neoplastic activity by interacting with thymidylate synthase (dUMP –> dTMP) and N5,N10-methylenetetrahydrofolate, blocking the transfer of a methylene group to the pyrimidine ring (via fluorine atom)
What is hydroxyurea’s effect on the formation of deoxyribonucleotides?
Deoxyribonucleotides are first formed by the reduction of ribonucleoside DIPHOSPHATE (ex. ADP –> dADP) via ribonucleotide reductase. Hydroxyurea inhibits ribonucleotide reductase.
Adenosine deaminase deficiency
Adenosine deaminase (adenosine –> inosine)
- deficiency will result in accumulation of adenosine
- adenosine is an immunosuppressant
- one cause of SCID (severe combined immunodeficiency) aka bubble boy disease
When is b-aminoisobutyric acid formed? This is a good marker for?
b-aminoisobutyric acid is formed during the breakdown of thymine (thymine –> dihydrothymine –> b-aminoisobutyric acid –> methlymalonyl coA)
-it is a good marker for cancer cell death during chemotheraphy
Gout is due to the precipitation of sodium urate crystals in joints and kidneys. What are the 2 enzymes if defected could lead to gout.
Deficiency in this enzymes result in increasing synthesis of PRPP/purines
-PRPP synthetase (ribose-5-phosphate + ATP –> PRPP + AMP) is abnormal and does not respond to feedback inhibition leading to increase PRPP
-HGPRT (hypoxanthine + PRPP –> IMP + PPi)
(guanine + PRPP –> GMP + PPi)
is partially defected leading to increase PRPP and more de novo synthesis of purines
Allopurinol’s biochemical effect and used to treat?
Allopurinol is used to treat gout. It is often given as a pretreatment for chemo b/c during chemo, large quantities of nucleotides are released from killed cancer cells, leading to uricemia and gout.
It will inhibit xanthine oxidase (hypoxanthine –> xanthine; xanthine –> uric acid)
-xanthine oxidase will make allopurinol into oxypurinol, which will bind tightly to xanthine oxidase, preventing it from binding to hypoxanthine or xanthine (suicide inhibition)
Lesch-Nyhan Syndrome
-hereditary X-linked recessive condition due to a SEVERE or COMPLETE deficiency of HGPRT activity
(reminder HGPRT is involved in purine salvage pathway:
hypoxanthine + PRPP –> IMP + PPi; guanine + PRPP –> GMP)
-gout and neurological issues including desire for self-mutilation.
