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104 Cards in this Set
- Front
- Back
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Full-term neonate, retarded, hyperactive with musty odor
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PKU
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What is the mechanism of hypoglycemia of a man who drinks 7 martinis before dinner?
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NADH increase from drinking prevents gluconeogenesis by shunting pyruvate and oxloacetate to lactate and malate.
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What are the symptoms of Kwashiorkor?
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Increased belly, failure to thrive, skin and hair depigmentation.
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Why whould an alcoholic develop a rash, diarrhea and altered mental status?
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Vitamin B3 deficiency
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What is alkapotonuria?
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black spots on sclera and black urine.
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Where is the defect in Familial Hypercholesterolemia?
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LDL receptor.
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What is the difference between Euchromatin and Heterochromatin?
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heterocromatin- Condensed, transcriptionally inactive
Euchromatin- less condensed, transcriptionally active. Eu=true. Condensed by (-) charged DNA looped around (+) charged H2A, H2B, H3, and H4 hsitone octamers (nucleosome bead). H! nucleosomes togeher in a string. Mitosis: DNA forms mitotic chromosomes. |
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Purines vs. Pyrimadines
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Purines
PURe As Gold Adenine and Guanine 2 rings. Adenine has Ammonia Pyrimidines CUT the PY Cytosine, Thymine, Uracil THYmine has a meTHYl GC (3 bonds) is stronger than AT (2 bonds) the more GC, the higher the melting point Nucleotides are linked by a 3,5 phosphodiesterase bond. |
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What is transition vs. transversion?
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TransItion = Identical (purine for purine or pyrimadine for pyrimadine)
TransVersion = conVersion between types. |
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Features of the genetic code
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Unambiguous- each codon specifies only 1 AA.
Degenerate- More than 1 codon may code for the same amino acids. Commaless, nonoverlapping Universal except mitochondria. |
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What are the major DNA mutations?
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Silent- Same AA, often a base change in the 3rd position.
Missense- Change in an AA (conservative is a similar AA) Nonsense- Stop codon is made, STOP the NONSENSE Neomorphic- additon of new abilities to a gene product's function Frame shift- the mutation leads to a shift in how the sequence is read. From a deletion or something the like. Amorphic- loss of gene product function Antimorphic- mutated protein acts to inhibit a normal protein. Hypomorphic- loss of a part of a gene function. |
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Quickly go through the cell cycle.
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Interphase- precedes mitosis, has G1, S, and G2
G1- Period of preparing for S phase. Cell growth- lipids and proteins. 12 hrs. Cyclin controls this. (Cyclin D phosphorylates Rb protein. malfunctionican leads to retinoblastoma) The cell can break off to G0 S- DNA replication and with de novo synth of DNA. 6-8 hrs. G2- Preparation for mitosis. Cyclin B regulates. 3-4 hrs. M- Mitotic phase of cell division. |
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What part of the cell cycle does Methotrexate affect?
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The S phase, where there is de novo synthesis of DNA and folate is required.
Methotrexate inhibits dihydrofolate reductase preventing the reduction of folic acid to tetrahydrofolate. This prevents methylation of dUMP to dTMP and synth of one-carbon moieties of purines. |
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What is the difference between permanent, stable and labile cells?
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Permanent cells- neurons, skeletal and cardiac muscle and erythrocytes stay in G0 till they die.
Stable- hepatocytes, lymphocytes. Stay in G0, but can be stimulated to leave. Labile cells- do not enter G0. Bone Marrow, epithelium, GI, hair. |
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What is Thyamine?
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Converted to thyamine phosphatase to help Pyruvate Dehydrogenase make acetyl CoA.
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What is the co-enzyme for:
Pyruvate Carboxylase Pyruvate Dehydrogenase |
Biotin
Thiamine |
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What is the biochem of Scurvy?
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Lack of Vit. C leads to impaired hydroxylation of proline residues in precollagen chains leading to weak vessels.
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Why use PCR and sequencing over Southern Blot?
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Southern blot is a gross look at DNA, cannot pinpoint a single base pair mutation.
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Breakdown Cystic Fibrosis
1. Gene defect 2. Clinical consequences |
Most common is an AR gene deletion
Clinically- deficiencies in pancreatic enzymes, pulm obstruction, and infection which causes destruction and respiratory failure. |
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What are the essential Amino Acids?
Which are Ketogenic, Glucogenic and Both? |
PriVaTe TIM HALL
Phenylalanine Valine Threonine Tryptophan Isoleucine Methionine Histidine Arginine (in kids for growth) Lysine Leucine Keto- LL Both- TIP (If you can do both, your more successful, more likely to tip) |
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What is the rate limiting enzyme of anaerobic metabolism in cardiac muscle?
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PFK-1 is the rate limiting enzyme for glycolysis which is the predominate sourse of ATP in anaerobic metabolism.
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How is Prokaryotic DNA replicated?
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One origin of replication with continuous replication on leading strand and discontinuous on lagging strand.
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What are Okazaki fragments?
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The fragments from lagging strand.
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What are the roles of the following:
Helicase Single Strand DNA binding proteins (SSB) DNA topoisomerases Primase DNA polymerase 3 DNA polymerase I DNA ligase |
Helicase- unwinds DNA
SSB- Bind to the single strands of unwound DNA to prevent reformation of the helix Topos- create a nick in the heilx to relieve supercoils Primase- Makes an RNA primer on which DNAP3 can replicate DNAP3- elongates the chain by adding DNs to the 3prime end until it reaches the preceeding fragment. (5->3)Exonuclease proofreads (3->5) DNAP1-degrades RNA primer, 5->3 Ligase- seals the deal. |
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What are the roles of the following in Glycogenesis:
Glycogen synthase Glucosyl transferase Insulin Glucagon Epinepherine UDP glucose |
Glycogenesis takes place in the cytoplasm of the liver, muscle, and adipose tissue.
Glycogen synthase adds glucose, 1,4 Glucosyl transferase creates a branching chain with 1,6 Insulin stimilates Glucagon and Epi inhibit through the cAMP protein kinase A phos. UDP glucose is the substrate for glycogen. |
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What are the roles of the following in glycogenolysis:
Glucose 1 Phosphate Glycogen phosphorylase Debranching enzyme Phosphoglucomutase Glucagon Epinephrine Insulin |
Glygogenolysis is in the cytoplasm of muscle, liver, and adipose
G1P is released to undergo glycolysis Glycogen phosphorylase breaks 1,4 debranching enzyme breaks 1,6 phosphoglucomutase converts g1p to g6p Glucagon and Epinephrine stimulate glycogenolysis. Phosporylates Glyogen phosphorylase. Insulin inhibits by dephosphorylating glycogen phosphorylase. |
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A 3-month-old presents with poor weight gain. She has mild hepatomegaly, enlarged tongue and EKG changes.
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Pompe Disease- AR Glycogen storage disease
Deficiency in lysosomal acid alpha 1,4- glucosidase an enzyme that degrades glycogen in lysosomal vacuoles. Can come on in infants (most severe). Leads to hyprtrophic cardiomyopathy, macroglossia. Juvenile- delayed motor milestones in walking and swallowing. adult- slowly progressive proximal muscle weakness. No cardiac symps in adults or juveniles. Labs- Elevated serum CK, Aspartate tansaminase. The only lysosomal accumulation of glycogen. |
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What is the role of lysosomal acid alpha 1,4- glucosidase?
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Degrades glycogen in lysosomal vacuoles.
Deficiency leads to pompe disease. |
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What is Cori Disease?
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AR disorder of glycogen debranching enzyme causing incomplete glycogen breagdwon. abnormal glycogen.
hepatosplenomegaly, hypoglycemia, hyperlipidemia, and growth retardation. skeletal myopathy and caridomyopathy. fasting ketosis. Rx- high carb diet (cornstarch) Jews of North Africa. |
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Why do Cori and Anderson go hand in hand?
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Cori is defeciency of the debranching.
Anderson is a branching deficiency leading to poor solubility of glycogen and cirrhosis. |
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A 24 y/o with painful muscle cramps on prolonged excercise with occasional reddish-purple urine. What is the Diagnosis? What is the deficiency?
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McArdle Disease- AR
Deficiency in muscle glycogen phosphorylase so the 1,4 cannot be broken. Leads to excercise intolerance, cramping, and burgundy-colored urine from muscle breakdown. Has elevated creatine kinase even at rest. |
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What is the difference between McArdle's and Tarui Disease?
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McArdle's is a breakdown deficiency. Tarui is an AR disorder that has a similar presentation, but his a defect in PFK so glycolysis is malfunctioning. Also has nausea and vomiting and hemolytic anemia.
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What is Pyruvate Dehydrogenase complex deficiency?
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AR disorder
PD coverts pyruvate to acetyl CoA. Without it, there is limited Citrate production and no citric acid cycle. This can lead to an energy defecit in the CNS, lactic acidosis. Neuro symps like ataxia, developmental delay, abnormal eye movements, and seizures. A Thiamine(B1) deficiency can bring it out (alcoholics). High blood lactate and pyrvate levels and lactic acidosis. Rx- give high fat foots with ketogenic nutrients. Lysine and Leucine |
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What does a deficiency in fructokinase cause?
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Essential fructosuria
AR disorder asymptomatic, but have sugar in blood and urine. Can be confused with DM. |
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How does Fructose Intolerance manifest itself?
What is the defect? What are the clinical symptoms? |
Fructose 1,6 bisphos aldolase B disorder in liver, kidney and intestine, AR.
This enzyme catalyzes the hydrolysis of F1P and F1,6BP Without this enzyme, F1P can accumulate and damage the liver. Fruit Juice, Fruit, Sweetened Cereal, or table sugar are the triggers Clinical Sx- lethargy, irritability, jaundice, hepatomegaly, vomiting, convulsions. Can cause cirrhosis and kidney failure. Labs, Hypoglycemia, fructosemia, liver and kidney signs. |
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When you think Mediterranean and anemia, what enzyme do you think of?
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G6P dehydrogenase
X-linked recessive. catalyzes O2 in the HMP shunt. Reduces NADP to NADPH. Maintains glutathione. w/o, lose RBCs. Fava beans, TB drugs and other triggers bring out the symps. Jaundice, gallstones, fatigue, splenomegaly. Normochromic, normocytic anemia. Heinz bodies. |
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What are the roles and regulators of the following in Glycolysis:
Hexokinase Glucokinase Phosphofructokinase Pyruvate kinase |
Glucagon inhibits all, Insulin Stimulates all.
Hexokinase and Glucokinase- Triggers Gcose to G6P. Inhibited by G6P. Hexokinase is all over, Gluco is only in the liver and pancreas. Gluco is inhibed by F6P not G6P. PFK- Rate limiting enzyme, triggers F6P to F16BP, inhibbed by ATP and Citrate. Stimmed by F26BP, AMP Pyruvate Kinase trigs Phospho to pyruvate. Inhibbed by ATP, Alanine. Stimmed by F16bp. |
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What is Phase 1 and Phase 2 glycolysis?
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Phase I- Energy invesment
1 Gcose to 2 G3P Consumes 2 ATP F6P to F16BP is the rate limiting step Phase II- Energy production phase Converts two G3P to two pyruvate makes 4 ATP and two NADH |
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What are the enzymes of glycolysis?
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Deficiency in any least to hemolytic anemia.
Hexokinase/Glucokinase PFK 1 Aldolase Triose Phosphate Isomerase G3PD Phosphoglycerate kinase Enolase Pyruvate Kinase |
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What are the 5 fates of Pyruvate?
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Acetly CoA- Enters the Crebs and makes Fatties. Pyruvate Dehydrogenase triggers it, cofactored with thiamine and Coenzyme A. In the mitochondria and is irreversible. ATP, NADH, and Acetyl-CoA are inhibitors.
Oxaloacetate- Used in the Crebs and gluconeogenesis. Triggered by Pyruvate Carboxylase with cofactor Biotin. Acetyl CoA can stimulate. Is an irreversible reaction in the Mitochondria. Lactate- made in conjuction to replenish NAD stores. Triggered by Lactate Dehydrogenase and high NADH/NAD ratio. Reversible reaction in teh cytosol of liver, heart and muscle. Alanine- serves as a carrier of amino acids in muscle to liver. ALT triggers. Ethanol- Yeast and Bacterial reaction to replenish NAD, triggered by Pyruvate decarboxylase. Uses Thiamine as cofactor. |
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how is fructose metabolized?
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Fructose to F1P to Dihydroxyacetone Phosphate or Glyceraldehyde
Dihydroxyacetone Phospate enters glycolysis Fructokinase triggers the first reaction. Deficiency causes essential fructosuria. Fructose 1 Phosphate Aldolase B triggers the second. Deficiency causes fructose intolerance. |
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How is galactose metabolized?
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Galactose to Galactose 1P to Glucose 1P to glycolysis or gluconeogenesis.
Galactose kinase triggers the first. Deficiency causes galactosemia and galactosuria, galacitol accumulation of galactos is present in diet. Uridyl transferase triggers the second reaction. Deficiency causes Galactosemia with an increase in galactitol. |
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What are the oxidative and non-oxidative parts to the pentose phosphate pathway?
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The pentose phosphate pathway is a reaction takes place in the liver, adrenals, and mammary glands. It works as an alt route for glucose oxidation without consuming ATP. It makes Ribose-5-p for nucleotide synth.
Oxidative is irreversible. Generates two NADPH which are used in Fatty synth and chol synth, and reduced glutathione for RBCs Nonoxidative- reversible reaction that generates intermediate molecules for nucleotide synth and glycolysis. |
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What are the major enzymes of gluconeogenesis?
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Pyruvate carboxylase- needs biotin. Activated by AcetylCoA. Inhibbed by ADP, takes place in mitochondria. Pyruvate to oxaloacetate
PEP carboxylase- needs GTP, inhibbed by ADP. Oxalo to Phosphoenolpyruvate F16BPatase- Activated by cAMP, glucagon, Inhibbed by AMP insulin, F26BP. F16BP to F6P. Glucose6P- G6P to Glucose. Enzymes are in liver, kidney, intestinal epi. NOT muscle. Deficiency of any enzyme (von Gierke's) causes hypoglycemia. |
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What is needed for gluconeogenesis?
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Two pyruvate
Four ATP and two GTP Two NADH Six H2O |
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What is the Cori Cycle?
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It transfers substrates of gluconeogenesis between muscle, RBCs and liver. Muscle can function anaerobically getting 2ATP.
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A 3-year-old sufferes from restlessness and fatigure. Fidgety between meals. Fat cheeks, "doll-like" face, protuberant abdomen.
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Von Gierke's Disease- AR deficiency in Glucose 6 Phosphatase which is needed for G6P to Glucose in gluconeogenesis.
Causes accumulation of glycogen in liver and kidney causing hepatomegaly. Labs- hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia Rx is cornstarch or glucose infusion. Decrease diet of fructose and galactose. Allopurinol to lower uric acid. |
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What diseases cause benign glycogenosis, and present with hepatomegaly, hypoglycemia, and ketosis?
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Hers- Liver phosphorylase deficiency.
Phosphorylase kinase deficiency. |
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What is Galactokinase Deficiency vs. Classic Galactosemia?
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Galactokinase- Benign AR deficiency of galactokinase, an enzyme that phosphorylates galactose into Galactose 1P. Leads to a build up of galactose in the eye.
Galactosemia- AR disorder of galactos1P uridyl transferase which converts Galac1P to G1P. Leads to build up of Galactose, galactitol, and galac1P in kidney, liver, lens, spleen, and brain Galactitol builds up and can cause entry of water into eye (lens) and cause a cataract. Galactokinase present only with the cataract. Galactosemia present with jaundice, hepatosplenomegaly, cataracts, and mental retardation. Screening for Galactosemia is done. |
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Breakdown lactase deficiency.
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Reduced lactase-phlorhizin hydrolase. Decreased lactose digestion. Causes diarrhea, abdominal pain and flatulence.
Rx- enzyme substitute. More common in blacks, asians. Also age dependant. |
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For pyruvate dehydrogenase what are the:
cofactors Reaction Activators |
Cofactors-
1. Pyrophosphate/Thiamine/B1 2. FAD (B2, riboflavin) 3. NAD (B3, niacin) 4. CoA (B5) 5. Lipoic Acid) Reaction- Pyruvate + NAD + CoA --> acetyl-CoA + CO2 + NADH Activated by excercise: Increase in NAD/NADH ratio, ADP, and Ca |
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What does the Crebs Cycle yield?
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2 CO2
3 NADH 1 FADH2 1 GTP Results in 12 ATP per acetyl coA. |
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What are the activators and inhibitors of these Crebs regulators:
Citrate synthase Isocitrate dehydrogenase Alpha ketoglutarate dehydrogenase |
Citrate- inhibbed by ATP, NADH, Succinyl CoA. Oxalo to Citrate
Isocitrate- ATP, NADH inhib, ADP activates. Iso to Alpha. Alpha- inhibbed by ATP, GTP, NADH, Succinyl coA. Alpha to Succinyl |
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Tell me this about the Citric Acid Cycle:
Where does it occur? Why are Succinyl CoA, Oxaloacetate, Alpha-ketoglutarate, and Citrate important biproducts? What are the major intermediates? |
1. CAC happens in the mitochondria.
2. Succinyl- heme Oxalo- gluconeo and AAs Alpha- AAs Citrate- Fatties Can I keep Selling Sex for Money Officer? Citrate Isocitrate Alpha Keto Succinyl CoA Succinate Fumarate Malate Oxaloacetate |
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What inhibits these parts of the Electron Transport chain:
Complex I Complex II Complex IV Complex V The H+ gradient |
Complex I- Amobarbital adn rotenone
Complex II- antimycin A Complex IV- CN, CO Complex V- Oligomycin (Increase the gradient, but no ATP) H+- 2,4-Dinitrophenol- increases permeability of membrane, decreases gradient, O2 still consumed. No ATP. |
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The Electron Transport Chain Fun Facts
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Complex I- FMN + 2NADH--> FMNH2
Complex II- FADH2 CoQ- goes from I,II to III Complex 3, cyt C, IV- Heme Complex IV- makes H2O |
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What are the malate and glycerophosphate shuttles?
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Malate- Oxeloacetate and NADH become Malate, enter the mitochondria and go back.
Glycertophosphate- DHAP and NADH become glycero, enter mitochondria and go back to DHAP and FADH2 ONLY 1.5 ATP!!! |
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Which amino acids are Aliphatic?
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aLIPhatic
VAG LIP |
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Which amino acids are Aromatic?
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Coach doesn't like their AROMA they get no PT(T)
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Which Amino Acids are Basic?
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HAL is the most BASIC version of the space odyssey computer
Arginine, Lysine, His. |
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What happens to amino acids at the body pH of 7.4?
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At body pH 7.4, Acidic amino acids Asp adn Glu are negatively charged; basic amino acids Arg and Lys are positively charged. His has no net charge.
Arg and Lys have an extra NH3 group and are found in high amounts in histones to bind to DNA which is negatively charged. |
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What is the process of transamination?
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Occurs in liver, muscle, kidney and other tissues.
Uses pyridoxal phosphate (B6) as a cofactor Deamination is the first step in amino acid metabolism. The aminotransferases act to remove the amino groups and transfer them to other molecules. Alanine Aminotransferase (ALT)- transfers from alanine to alpha-keto to form glutamate Aspartate Aminotransferase- (AST)- transfers from Glutamate to Oxaloacetate to form Aspartate |
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What is the process of oxidative deamination?
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Takes place in liver and kidney
Cofactors are NAD or NADP Deamination is the first step in AA metabolism. Glutamate dehydrogenase removes the amino group from glutamate. ATP, GTP inhib glutamate dehydrog. ADP and GDP activate. |
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What does the Urea cycle produce?
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Urea
Fumarate H2O |
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Give the following info about the urea cycle:
What's the purpose? Where does it occure? What regulates it? What AAs comprise it? What happens with a deficiency? |
The Urea cycle transforms NH4 into urea for excretion.
Occurs in the liver, corbamoyl phosphate is in the mitochondria, the rest is in the cytosol Carbamoyl phosphate synthetase I is activated by N-acetylglutamate. Ordinarily, Careless Crappers Are Also Frivolous About Urination Ornithine Carbamoyl phosphate (added in) Citruline Aspartate (added in) Argininosuccinate Fumarate (secreted) Arginine Urea (excreted) Deficiency causes Hyperammonemia. Leads to CNS deterioration with mental retardation, seizure, coma and death. |
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What are the substrates of the Urea Cycle?
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NH3, CO2 (together form Carbamoyl phosphate), Aspartate, 3 ATP, H2O
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What are the derivatives of Tyrosine?
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Thyroid hormones
Dopa- Melanin, Dopamine, NE, Epi (Tyrosine comes from Phenylalanine) |
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What are the derivatives of Methionine?
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S-Adenosylmethionine
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What are the derivatives of Tryptophan?
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Niacin --> NAD/NADP
Serotonin Melatonin |
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What are the derivatives of Glutamate?
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GABA
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What are the derivatives of Glycine?
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Porphyrin (heme synth)
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What are the derivatives of Arginine?
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Creatine
NO Urea |
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What are the derivatives of Histidine?
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Histamine
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What are the derivatives of Phenylalanine?
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Tyrosine
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How is phenylalanine metabolized?
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It is converted to Tyrosine by Phenylalanine hydroxalase with Tetrahydrobiopterin (THB) as a co-factor. Dihydropteridine reductase replenishes the THB.
Deficiency in Phenylalanine hydrox or THB results in Phenylketonuria (PKU) It is also metabbed to Phenylpyruvate by Aminotransferase. |
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A 25 y/o presents with pain and swelling in his knees. He has dark spots on his conjunctiva and nasal bridge. Urine turns black when left standing.
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Alkaptonuria- AR disorder with defective formation of homogentisic acid oxidase (chromosome 3)
The enzyme degrades tyrosine. Accumulation of homogentisic acid occurs which degenerates cartilage causeing a dark blue connective tissue (Ochronosis) and degenerative joint desease. Increased pigment of ears, nasal bridge, conjunctiva, neck and ant thorax. Arthritis. Dark Urine from homogentisate polymers (alkapton bodies). Rx- treat arthritis. |
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14 y/o boy with fever, intermittent flaank pain with nausea and vomiting. Tachy. radio opaque stones.
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Cystinuria- AR disorder with a bad AA transporter in the renal tubule.
Cysteine is increased in the urine causing kidney stones and hematuria. Radiopaque kidney stones Rx- low methionine diet, acetazolamide to alkanize the urine you get rid of COLA Cysteine Ornithine Lysine Arginine |
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What is Cystinosis and Fanconi Syndrome?
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Cystinosis- rare disorder characterized by the intralysosomal accumulation of cysteine.
Fanconi- AR, infantile form of cystinosis. renal proximal tube dysfunction--> hypophosphatemia, renal glycosuria, AAciduria, and hypokalemia. Clinically- growth retard, vomit, rickets, polyuria, metabolic acidosis, photophobia. Death by 10 of infection or uremia. |
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What AAs are lost in Cystinuria?
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COLA
Cysteine Ornithine Lysine Arginine |
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32 y/o with rash on face and neck. Worse when outside. He is irritable. He has an ataxic gate, photophobia, and a red, scaly rash.
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Hartnup Disease- AR mutation of Na-dependant transport of AAs (tryptophan)
This channel is in the proximal tubule of the nephron and the brush border of the small intestine. Can mimic niacin deficiency (tryptophan is a precursor). Sx- photosensitive dermatitis and neuro signs- Personality disturbances, photophobia, retard, ataxia Labs- renal aminoaciduria Rx- give niacin. |
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7 y/o with decreased vision. Southeast Asian. Lenticular dislocation on eye exam and long fingers. Behind in milestones with mild retardation.
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Homocystinuria- AR disorder with defect in cystathionine synthase or N-methyl tetrahydrofolate homocysteine methyltransferase, or a decreased affinity of the synthase for pyridoxal phosphate (B6) a cofactor.
Homocysteine is toxic to vascular endothelium--> increased atherosclerosis and increased platelet adhesion and thrombus formation. Clinically- marfanoid appearance, mental retard, osteoporosis, lens dislocation, risk of thrombo. Labs- increased methionine in serum, homocysteine in urine. Rx- decreased methionine in diet, increased cysteine and folate. With decreased affinity, high-dose B6. |
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How is homocysteine dealt with by the body?
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Converted to methionine by NPTHM or to cystathionine by cystathionine synthase.
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What will happen with a cystathionine synthase or NPTHM deficiency? If cystathione has a decreased affinity for B6?
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Homocystinuria
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4 day old boy puking breast milk, regularly urinating syrup odored pee. Rigid muscle tone and no Moro reflex.
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Maple Syrup Urine Disease- defect of the branched chain alpha keto dehydrogenase complex.
This helps breakdown isoleucine, leucine, and valine. This causes acidosis, and can be toxic to the brian causing edema, and demylenation. Rx- dialysis, thiamine, restricted diet. I Love Vermont maple syrup Isoleucine Leucine Valine |
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2 y/o foreigner. small with slight microcephaly. Developmental delays. Hypertonia and hyperreflexia.
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Phenylketonuria- AR disorder with mutation of alanine hydroxylase, or decreased tetrahydrobiopterin (a cofactor)
Without this enzyme there is a build up in phenylalanine and a decrease in tyrosine. This can cause severe brain damage, decreased myelin production, dopa production, melanin production. Clinically- growth retardation, decreased pigmentation, musty urine, body odor (Phenyl is aromatic), hypertonia, hyperreflexia. Phenylketones in urine. Rx- Decrease intake of phenylalanine (aspartme in Nutrasweet) and increased dietary tyrosine. |
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What is Histidinemia?
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AR deficiency in histidine alpha deaminase. Increased histidine in blood with hearing and speech defecits.
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How does Albinism develop?
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1. Tyrosinase deficiency- cannot synth melanin from tyrosine
2. Defective tyrosine transporter (decreased tyrosine) This can also be caused by lack of migration of neural crest cells. Lack of melanin = increased risk of skin cancer. |
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What are the origins of the atoms in the pyrimidine ring?
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Aspartate- C4,5,6 and N1
Carbamoyl phosphate- C2, N3 |
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What are the origins of the purine rings?
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Girl Fights Are Catty. Guy Fights, Genuine
Glutamine- N3 Formyl Tetrahydrofolate- C2 Aspartate- N1 CO2- C6 Glycine- C4,5 N7 Formyl Tetrahydrofolate- C8 Glutamine- N9 |
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Breakdown de Novo Purine Synthesis:
Substrates Products |
Occurs in all tissues
Substrates- Ribose 5-P, glycine, glutamine, ATP, CO2, aspartate Products- GMP, AMP, glutamate, fumarate, H2O |
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What are the regulatory enzymes of de Novo Purine Synthesis?
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Phosphoribosylpyrophosphate (PRPP) synthetase- AMP, IMP and GMP inhib.
Glutamine PRPP amidinotransferase- Catalyzes the committed step. Inhibbed by AMP, IMP, GMP IMP dehydrogenase- Inhibbed by GMP Adenylsuccinate synthetase- Inhibbed by AMP. |
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What pharm can inhibit de Novo Purine Synth?
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MTX can inhibit by inhibiting tetrahydrofolate production.
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Breakdown the purine salvage pathways:
Hypoxanthine Guanine Adenine |
All reactions use PRPP as a substrate.
Hypoxanthine and Guanine- Regulated by Hypoxanthine-guanine phosphoryibosyltransferase (HGPRT). Inhibbed by IMP and GMP. Adenine- Regulated by Adenine Phosphoribosyltransferase. Inhibbed by AMP. Deficiency of HGPRT- Lesch-Nyhan syndrome |
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How are purines degraded?
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GMP->Guanosine->Guanine->Xanthine->Uric Acid
AMP->Adenosine->Inosine->Hypoxanthine->Xanthine->Uric Acid Adenosine Deaminase (ADA)- converst Adenosine to Inosine Xanthine Oxidase- Conversts xanthine to uric acid. Purine nucleoside phosphorylase- Converts nucleosides into purine base forms (R-1-P) ADA deficiency- Severe Combined immunodeficiency disease (SCID) Allopurinol- blocks xantine oxidase for Gout treatment. |
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What are the substrates and products of de novo pyrimidine synthesis?
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Occurs in all tissues
Substrates- CO2, glutamine, ATP, aspartate, NAD, PRPP Products- UTP, CTP, glutamate, NADH, CO2 |
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What are teh regulatory enzymes of de novo Pyrimidine Synthesis?
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Carbamoyl phosphate synthetase II- Inhibbed by UTP, Activated by ATP, PRPP.
Orotidlyate decarboxylase- Inhibbed by UMP and CMP CTP synthetase- Inhibbed by CTP Deficiencies in Orotate phosphoribosyl transferase or OMP decarboxylase- orotic aciduria- growth retard and anemia. |
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What is the salvage pathway for Pyrimidines?
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Pyrimidines can be salvaged from Orotic Acid, uracil, and thymine, but NOT from Cytosine.
C is OUT Enzyme- Pyrimidine phosphoribosyltransferase |
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How are pyrimidines degraded?
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UTP, CTP, TTP
Can be broken down into precursors or intermediates for citric acid cycle. UC->Acetyl coA T->Succinyl CoA Other products are CO2, NH4, Beta-alanine, Beta-aminobutyrate. |
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2-month-old male. Failure to thrive and repeated infections, bacterial, viral, fungal. Low leukocyte count
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Adenosine Deaminase (ADA) Deficiency- AR defect of ADA
converts adenosine to inosine. W/o ADA, adenosine accumulates-> increase of dATP which inhibits ribonucleotide reductase-> decrease in DNA synth-> dysfunctional T and B cells Clinical- Severe Combined Immunodeficiency- SCID. Can present with Pneumocystis carinii. GVHD with transfusions. Rx Bone marrow transplant, exogenous ADA, and gene therapy are possible, but not too affective. Will die w/in 1 year. (Bubble boy) |
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What gene defects can cause severe combined immunodeficiency?
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AR-
ADA defect RAG-1 or RAG-2 mutations in tyr kinase gene. X-linked recessive- defective IL-2 receptor on T-cell. |
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2 y/o- bites himself, writhing body movements. Hyperreflexia, reddish-orange urine
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Lesch-Nyhan Syndrome
X-linked recessive deficiency of HGPRT. HGPRT converts Guanine and hypoxanthine to GMP and IMP. W/o enzyme, they are degraded to uric acid causing hyperuricemia. Excess purines are made as de novo synth is triggered. This can cause CNS damage. Clinically- Self-mutilative behavior, agression, choreoathetosis, kidney stones, gout, mental retard, orange urine. Rx- Allopurinol will prevent uric acid, but not prevent behavior change and CNS damage. A partial deficiency can cause gout. LNS- Lacks Nucleotide Salvage |
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2 month old- with hypochromic megaloblastic anemia, unresponsive to Fe, Folate, and B12 Rx. Small with sparse hair, pale, lethargic.
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Orotic Aciduria- AR disorder in UMP synthase.
UMP coverts orotic acid to UMP. W/o, there is deficient hematopoiesis and growth. Labs- Orotic acid crystalluria, hypochromic megaloblastic anemia Rx- Uridine and Cytidine |
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What are the enzymes of Deoxyribonucleotide Synthesis?
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Ribonucleotide reductase- reduce ribo to deoxyribo. Thioredoxin gives reducing power.
Thioredoxin reductase- restores thioredoxin. dATP inhibits ribonucleotide reductase. |
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What are the regulatory enzymes of Thymidylate synthesis?
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Thymidylate synthase catalyzes a reaction in which a carbon is transfered from FH4.
Dihydrofolate reductase- regenerates FH4 Serine- remethylates to FH4 MTX- inhibs dihydrofolate reductase. |
