Flashcards in Biochemistry Deck (326)
Which histone is not in the nucleosome core?
Which makes DNA active and which makes it less: methylation and acetylation?
More active - acetylation, less active - methylation
Which bases are purines and which are pyrimidines?
Purines - AG, Pyrimidines - CUT
AAs required for purine synthesis
Glycine, Aspartate, Glutamine
AAs required for pyrimidine synthesis
Main branch point for both pyrimidine and purine synthesis
What pathways is carbamoyl phosphate involved in?
De novo pyrimidine synthesis and the urea cycle
OTC involved in urea cycle. Leads to increase in carbamoyl phosphate which is converted to orotic acid (pyr and pur synthesis)
What does hydroxyurea inhibit?
Does each of the following inhibit purine or pyrimidine synthesis? 6-MP, 5-FU, MTX, Trimethoprim
6-MP is purine, the others are all pyrimidine
Defects that cause orotic aciduria (2) and the genetics
Orotic acid phosphoribosyltransferase or orotidine 5-phosphate decarboxylase. AR
How do we distinguish between orotic aciduria and OTC deficiency?
OTC deficiency includes signs of hyperammonemia (due to backflow into urea cycle). No hyperammonemia in orotic aciduria
Treatment for orotic aciduria
Uridine (inhibits carbamoyl phosphate synthase II)
ADA deficiency causes feedback inhibition of what enzyme?
What will be present in high levels in the blood and what enzyme will be hyperactive in Lesch-Nyhan?
Uric acid present in high levels (failure to salvage). PRPP will be hyperactive (must make all new purines)
Retardation, self-mutilation, aggression, hyperuricemia, gout, choreoathetosis
Genetics of Lesch-Nyhan
Prokaryotic DNA polymerases and their functions
DNA pol 3 - synthesizes 5 to 3, proofreads 3 to 5. DNA pol 1 - removes RNA primers 5 to 3.
Defect in xeroderma pigmentosum
Excision of thymine dimers (failure of nucleotide excision repair)
Give the actors in base excision repair in order
1) Glycosylase, 2) Endonuclease and lyase, 3) DNA pol, 4) Ligase
Defect in HNPCC
Failure of mismatch repair
Defect in ataxia telangiectasia
Failure of nonhomologous end joining (a type of DNA repair)
What direction is mRNA read? What direction does protein synthesis occur in?
mRNA read 5 to 3. Protein synthesis is N to C
mRNA stop codons and what are they recognized by?
UGA, UAA, UAG. Recognized by releasing factors
Common sequences in promoters
AT-rich (TATA, CAAT)
What do each of the eukaryotic RNA pols make?
RNA pol 1 - rRNA (in the nucleolus), RNA pol 2 - mRNA, RNA pol 3 - tRNA
What does alpha-amanitin (in death cap mushrooms) inhibit and what is the effect of this?
RNA pol 2. Causes liver failure
Which end are the cap and poly-A tail respectively put on in mRNA?
Cap is 5 prime, poly A tail is on 3 prime end
What steps of mRNA processing take place in the cytosol?
Addition of 7-MG to 5 prime cap and interaction with P bodies
What do snRPs do and what disease can include antibodies to them?
Form splicosome. SLE
What effect do lactose and glucose have on the lac operon respectively?
Lactose - inhibits the repressor (expression of lac operon), Glucose - inhibits the activator (no expression of lac operon)
What bacteria are notable for having the lac operon?
What sequence on tRNA holds the AA and which end of the tRNA is it on?
CCA on the 3 prime end
What drugs inhibit DNA gyrase (prokaryotic topoisomerase 2)?
What drugs bind 30S and prevent attachment of aminoacyl-tRNA?
What molecule is necessary for tRNA charging and what is necessary for tRNA translocation?
Charging - ATP, translocation - GTP
What drugs bind 30S and inhibit formation of initiation complex and cause misreading of mRNA?
What drugs inhibit 50S peptidyl transferase?
What drugs block translocation during translation?
What drugs block peptide bond formation during translation?
Clindamycin and chloramphenicol
What is the 16S subunit, what is it part of, and what does it do?
Part of 30S, contains a sequence complementary to mRNA for translation initiation
Rb and p53 inhibit transition from what to what?
G1 to S phase
Two examples of stable cells
Hepatocytes and lymphocytes
What type of muscle is not permanent (ie can divide)?
What happens in RER and what cells have lots of RER?
Synthesis of exported proteins and N-linked oligosaccharide addition. Mucus-secretion goblet cells (SI) and plasma cells
What part of the neuron are nissl bodies in and what are they?
They are RER. In dendrites but not axons
What do SER do and give an example of something that would lead to more SER in liver
Steroid synthesis and detox of drugs and poisons. Polypharmacy will do it.
Protein modification in golgi
Modifies N-oligosaccharides on aspargine. Adds O-oligosaccharides on serine and threonine
Vesicular trafficking proteins (3) and what each does
COPI - retrograde (golgi to ER), COPII - anterograde (RER to cis-golgi), Clathrin - trans-golgi to lysosomes, PM to endosomes
Coarse facial features, clouded corneas, restricted joint movements
I-cell disease. Will see high plasma levels of lysosomal enzymes
Where are chondroiton and heparan formed and where does sulfation of tyrosine occur?
Where are very long FAs beta oxidized?
Between dynein and kinesin, which is retrograde and which is anterograde?
Kinesin - anterograde, Dynein - retrograde
What drugs act on microtubules?
Mebendazole and Thiabendazole (antihelminthic), Griseofulvin (antifungal), Vincristine and vinblastine (anticancer), Paclitaxel (anti breast cancer), Colchicine (anti gout)
Kartageners is a defect in what?
How do ciliated cells communicate?
Infertility, bronchiectasis, sinusitis, situs inversus
What disease is glial fibrillary acid protein (GFAP) a marker for?
Alexander disease (17q21 mutation, developmental delay, macrocephaly, seizures, hydrocephalus, dementia, spasticity)
3 main methods of protein degradation
Proteosome (ubiquitin), Lysosome, Calcium-dependent enzymes
Give the cancer(s) associated with each of the stainable intermediate filaments
Vimentin - sarcomas and some carcinomas, Desmin - rhabdomyosarcoma, leiomyoma, Cytokeratin - carcinomas, some sarcomas, GFAP - astocytoma, Neurofilaments - adrenal neuroblastoma
Inhibits Na-K pump by binding to K site
What is the most abundant AA in collagen?
Pattern in preprocollagen
Gly-X-Y (X and Y are proline, hydroxyproline or hydroxylysine)
Which step of collagen synthesis requires Vitamin C?
Hydroxylation of proline and lysine
Which steps of collagen synthesis occur where?
ER - synthesis, hydroxylation and glycosylation (triple helix formation), Extracellular - C-terminal cleavage (tropocollagen), Cross-linking (by lysyl oxidase)
What class of drugs inhibits collagen synthesis?
Genetics of osteogenesis imperfecta
Type 1 - AD (most common). Type 2 - AR (fatal early)
Name a disorder that includes hearing loss and dental imperfections
What is wrong with the type 3 collagen in ehlers-danlos?
Defective extracellular cleavage at the N and C termini makes it more soluble and less crosslinked
Genetics of Alport and what is the deficiency?
Abnormal type 4 collagen. X recessive
Hereditary nephritis, deafness, ocular disturbances
Alport. Ocular disturbances due to lenticonus (thinning of lens capsule)
What AAs are prevalent in elastin?
Proline and glycine (both nonglycosylated)
Wrinkles of aging are due to what?
Reduced collagen and elastin production
What type of emphysema is seen in a1 antitrypsin deficiency?
Give the targets of Southern, Northern, and Western blots. Briefly describe Southwestern blotting.
Southern - DNA, Northern - RNA, Western - Protein. Southwestern blotting finds TFs
Inducibly manipulating genes using antibiotic-controlled promoters
Heteroplasmy relates to what kind of DNA?
What chromosome contains the gene for Prader-Willi and Angelman and which parental copy is deleted in each?
15. Paternal deleted in PW, Maternal deleted in Angelman
MR, hyperphagia, obesity, hypogonadism, hypotonia
MR, seizures, ataxia, inappropriate laughter
Hypophosphatemic rickets pathophys and genetics
X linked dominant. Increased phosphate wasting at proximal tubule
What characterizes mitochondrial myopathies on microscopy?
Ragged red fibers
Genetics and defect in achondroplasia
FGF receptor 3. AD. Associated with advanced paternal age
What gene is most commonly mutated in ADPKD and what chromosome is it on?
PKD1. Chromosome 16
Common complications of ADPKD
Polycystic liver disease, berry aneurysms (due to HTN), MVP
Genetics and defect (include chromosome if you know it) in FAP
APC gene (chr 5), AD
Genetics and defect in hyperlipidemia type IIA
LDL receptor defect, AD.
Genetics of Osler-Weber-Rendu
Telangiectasia, recurrent epistaxis, skin discoloration, AVMs
Osler-Weber-Rendu (Hereditary hemorrhagic telangiectasia)
Genetics and defect in hereditary spherocytosis
AD defect in spectrin or ankyrin
Genetics and defect (include chromosome if you know it) in Huntingon. Also what are the NT levels like?
AD. Chromosome 4. Low levels of GABA and ACh
Genetics and main complications of Marfan
AD. Aortic incompetence and dissecting aortic aneurysms. Floppy mitral valve, subluxation of lenses
Genetics and defect (include chromosome if you know it) in MEN
AD. 2A and 2B associated with ret gene
Genetics and defect (include chromosome if you know it) in NF-1
AD. Chromosome 17
What disorder includes lisch nodules and what are they?
NF-1. Pigmented iris hamartomas
Genetics and defect (include chromosome if you know it) in NF-2
AD. Chromosome 22
What disorder includes bilateral acoustic schwannoma and juvenile cataracts?
Genetics of tuberous sclerosis
Facial lesions, hypopigmented spots, cortical and retinal hamartomas, seizures, MR, renal cysts and angiomyolipomas, cardiac rhabdomyomas, astrocytomas
Genetics and defect (include chromosome if you know it) in VHL
VHL gene (a TS) on chromosome 3p
Hemangioblastomas on retina, cerebellum and medulla. RCC, constitutive expression of HIF and angiogenic growth factors
List AR disorders (10)
Albinism, ARPKD, CF, glycogen storage disorders, hemochromatosis, mucopolysaccharidoses (except Hunter), PKU, sickle cell, sphingolipidoses (except Fabry), thalassemias
Genetics and defect (include chromosome if you know it) in CF
CFTR gene (chr 7), AR
Common pulmonary infections in CF
Pseudomonas and S aureus
What type of channel is CFTR?
An ATP-Gated channel
Why do males with CF have infertility?
Bilateral absence of vas deferens
Treatment for CF
N-acetylcystein to loosen mucous plugs
List X recessive disorders (10)
Brutons, Wiskott-Aldrich, Fabrys, G6PD def, Ocular albinism, Lesch-Nyhan, Duchennes, Beckers, Hunters, Hemophilia A and B
What type of mutation occurs in duchennes?
X-linked frame-shift mutation (leads to deletion of dystrophin gene)
First muscles affected in duchennes
Hip muscles (hence Gowers sign)
Genetics and defect (include chromosome if you know it) in Fragile X
FMR1 gene is incorrectly methylated (X chr).
Macroorchidism, long face with large jaw, larage everted ears, autism, MVP, MR
What are the repeats in Fragile X, Friedreichs, Huntingtons, and Myotonic dystrophy respectively?
Fragile X - CGG, Friedreich - GAA, Huntington - CAG, Myotonic dystrophy - CTG
AFP levels in common in trisomies and NT defects
Trisomies 21 and 18 - low. Trisomy 13 - normal. NT defect - high
Trisomy 21 and 18 both have low AFP levels. What is the best way to differentiate them?
B-hCG. High in 21, Low in 18
In what instance would you see increased nuchal translucuency in utero
What is the in utero defect associated with high Inhibin A levels?
Flat facies, prominant epicanthal folds, simian crease, gap between 1st 2 toes, duodenal atresia, congenital heart diseaes
Most common complications of Downs syndrome
Duodenal atresia, septum primum, ASD, ALL, Alzheimers
What cause of Down syndrome has no maternal association?
Mosiacism. The other two causes are nondisjunction and robertsonian
Severe MR, rocker bottom feet, micrognathia (small jaw), low set ears, clenched hands, prominent occiput, congenital heart disease. Death within 1 year of birth
Edwards (trisomy 18)
Severe MR, rocker bottom feet, microphthalmia, microcephaly, cleft lip and palate, holoprosencephaly, polydactyly. Death within 1 year.
Pataus (trisomy 13)
Microcephaly, moderate to severe MR, epicanthal folds, VSD
Cri-du-chat (also high pitched cry, but that makes it too easy)
Deletion in cri du chat
Short arm of 5
Abnormal facies, MR, hypercalcemia, extreme friendliness, cardiovascular problems
Williams syndrome (microdeletion of chr 7 which includes elastin gene)
Defects in DiGeorge
CATCH-22. Cleft palate, Abnormal facies, Thymic aplasia, Cardiac defects, Hypocalcemia
Fat soluble vitamins
Water soluble vitamins (9)
B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B12 (cobalamin), C (ascorbic acid), Biotin, Folate
What compound prevents squamous metaplasia?
What can Vit A be used to treat (2)
AML (subtype M3) and Measles
Vit A deficiency
Night blindness, dry skin
Vit A excess
Arthralgias, fatigue, headaches, skin changes, sore throat, alopecia
Enzymes which require B1 (4)
Pyruvate dehydrogenase (glycolysis), Alpha-ketoglutarate dehydrogenase (TCA), Transketolase (HMP shunt, cytosolic), Branched-chain AA dehydrogenase
Classic triad of Wernicke-Korsakoff
Confusion, ophthalmoplegia, ataxia. Also shows up with confabulation, personality change, memory loss
Wernicke-Korsakoff results from damage to what structures?
Medial dorsal nucleus of thalamus and mammillary bodies
Polyneuritis, symmetrical muscle wasting
High output cardiac failure (dilated cardiomypoathy), edema
Cheilosis, corneal vascularization. NB - FAD (cofactor for succinate dehydrogenase) and FMN are derived from riboflavin
What is Vit B3 (niacin) used for and what can it be derived from?
Use in redox reactions (with NAD+ and NADP+), can be made from tryptophan
Vit B3 (niacin) deficiency
Pellagra - Diarrhea, Dermatitis, Dementia. Also glossitis
What can cause Vit B3 deficiency (3)
Hartnup disease (will also have pruritic rash, ataxia, loose stools), Malignant carcinoid, INH
Functions of Vit B5
Component of CoA and FA synthase
Vit B5 deficiency
Dermatitis, enteritis, alopecia, adrenal insufficiency
What compound can increase peripheral metabolism of levodopa?
Vitamin B6. NB - Vit B6 is required to make niacin (B3) from tryptophan
Functions of Vit B6
Transamination, decarboxylation, glycogen phosphorylase. Synthesis of cystathionine, heme, niacin, GABA
Vit B6 deficiency
Convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemia
What drugs can induce B6 deficiency?
INH and oral contraceptives
Macrocytic, megaloblastic anemia, hypersegmented PMNs, neurologic symptoms
Vit B12 deficiency
Methylmalonic acidemia is a defect in isomerization of what to what?
Methylmalonyl CoA to succinyl CoA (which requires B12)
What is the most common vitamin deficiency in the US?
Folic acid. Especially common in alcoholism and pregnancy
Why is IM Vit B12 given before a Shilling test?
To fill body stores of B12 so any absorbed B12 will end up in urine (where it can be measured)
Interpret the following Shilling test results (all numbers given are percentages): 1) D1 > 5, 2) D1 5
1 is normal. 2 is not pernicious anemia (may be fishworm, whipple, sprue, enteritis, etc). 3 is pernicious anemia
When we make methionine 3 compounds get converted to 3 other compounds. What are they?
Homocysteine to methionine. Methylcobalamin to cobalamin. 5-methyl THF to THF
Homocysteine can be used to make methionine. If we are deficient in B12 or Folate however, what other path does homocysteine go down?
Homocysteine to Cystathione to Cystine (requires B6)
What is the main methyl donor?
Biotin is a cofactor for what enzymes (3)
Pyruvate carboxylase, Acetyl-CoA carboxylase, Propionyl-CoA carboxylase
Symptoms and main causes of Biotin deficiency
Dermatitis, alopecia, enteritis. Antibiotic use or excessive ingestion of raw eggs.
What vitamin facilitates iron absorption?
What is necessary for converting dopamine to NE?
Swollen gums, bruising, hemarthrosis, anemia, poor wound healing
Scurvy (vit c deficiency)
Nausea, vomiting, diarrhea, fatigue, sleep problems, iron toxicity.
Vitamin C excess
What electrolyte abnormality usually leads to tetany?
Two vitamins that are not in breast milk and should be supplemented
Vitamin D and Vitamin K
Hypercalcemia, hypercalciuria, loss of appetite, stupor. May be associated with sarcoidosis
Vitamin D excess
What is the main function of Vitamin E?
Protect RBCs and PMs from oxidation damage
Hemolytic anemia, muscle weakness, posterior column and spinocerebellar tract demyelination
Vitamin E def
Vitamin K dependent factors
2, 7, 9, 10, Proteins C and s
Delayed wound healing, hypogonadism, decrease in adult hair, dysgeusia, anosmia
Zinc deficiency (5)
Deficiency of what vitamin may predispose to alcoholic cirrhosis?
Antidote for methanol or ethylene glycol poisoning
Why do you get increased ketone and FA production in alcoholism?
Depletion of oxaloacetate (pyruvate diverted to lactate by low NAD+) shuts down TCA and diverts aCoA into ketones. Overproduction of malate increases NADPH and thus FA synthesis
What regenerates the NAD+ consumed in glycolysis from G3P --> 1,3BPG?
Pyruvate --> Lactate
Complete malnutrition leading to tissue and muscle wasting, loss of fat, variable edema (not nearly as much edema as kwashiorkor)
Give the rate limiting enzymes for the following: Glycolysis, Gluconeogenesis, TCA cycle, Glycogenolysis
PFK-1, F-1,6-Bisphosphatase, Isocitrate dehydrogenase, Glycogen phosphorylase
Give the rate limiting enzymes for the following: De novo pyrimidine synthesis, De novo purine synthesis, Urea cycle, FA synthesis, FA oxidation, Ketogenesis
Carbamoyl phosphate synthetase 2, Glutamine-PRPP amidotransferase, Carbamoyl phosphate synthetase 1, Acetyl-CoA carboxylase, Carnitine acyltransferase 1, HMG-CoA synthase
Acetyl-CoA is an allosteric activator of what pathway?
Gluconeogensis. This is because it stimulates pyruvate --> oxaloacetate. This can then go to PEP and eventually back up to glucose
What are the two main universal electron acceptors associated with vitamins and which vitamins is used to make each?
NAD+ (from Vit B3) and FAD+ (from Vit B2)
4 main uses of NADPH
1) Anabolic processes, 2) Respiratory burst, 3) P-450 system, 4) Glutathione reductase
What induces and inhibits hexokinase and glucokinase respectively?
Hexokinase - uninduced and inhibited by G-6-P. No induction. Glucokinase - Induced by insulin, no inhibition
What enzyme allows the liver to serve as a blood glucose buffer
Glucokinase. Also acts like a glucose sensor in B cells
In contrast to a previous card, something inhibits glucokinase. What is it?
What things activate or inhibit the rate limiting step in glycolysis (PFK-1)?
Activate - AMP, Fructose-2,6-BP. Inhibit - ATP, Citrate
What things inhibit or activate pyruvate kinase (PEP to Pyruvate)?
Inhibit - ATP, Alanine, Activate - Fructose-1,6-BP
What things inhibit or activate pyruvate dehydrogenase (pyruvate to acetyl-CoA)
Inhibit - ATP, NADH, Acetyl-CoA. No activators
What enzyme allows us to make use of fructose if fructokinase is deficient?
Hexokinase (converts fructose to f-6-p, just like it does with glucose)
Which fructose related enzyme and its product are active in fed state? Which in fasting state? What protein regulates this process?
Fed state - PFK-2 makes more Fructose-2,6-Bisphosphate. Fasting state - Fructose Bisphosphatase 2 makes more Fructose-6-Phosphate. Protein Kinase A (resulting from insulin/glucagon) regulates this
Cofactors required for pyruvate dehydrogenase complex
Pyrophosphate (from B1, thiamine), FAD (from B2), NAD (from B3), CoA (from B5), Lipoic acid
What does arsenic inhibit and what are the findings in arsenic poisoning?
Lipoic acid (part of pyruvate and alpha-ketoglutarate dehydrogenase complexes). Findings are vomiting, rice water stools, garlic breath
Purely ketogenic amino acids
Lysine and Leucine
Which promotes glycolysis, high or low levels of Fructose-2,6-bisphosphate?
What are the four potential outcomes for a pyruvate molecule?
1) Alanine (carry AAs to liver), 2) Oxaloacetate (gluconeogenesis or TCA), 3) Acetyl-CoA (TCA), 4) Lactate (regenerate NAD+)
Deficiency of B1, B2, B3, B5 or Lipoic acid will stop what two steps related to the TCA?
Pyruvate dehydrogenase (pyruvate to acetyl-CoA) and a-KG dehydrogenase (a-KG to Succinyl CoA)
GTP generated in what step of the TCA can be used to regenerate PEP and start gluconeogenesis?
Succinyl-CoA to Succinate
Major ox phos poisons and the category of each
Cyanide and CO - electron transport inhibitors. Oligomycin - ATP synthase inhibitor. Aspirin and 2,4-DNP - Uncoupling agents
Where does gluconeogenesis occur (organs)?
Liver, kidney, intestinal epithelium
Irreversible enzymes required for gluconeogenesis (4)
Pyruvate carboxylase (biotin), PEP carboxykinase, Fructose-1,6-bisphosphatase, G-6-Phosphatase
Cholesterol synthesis requires what other biochemical pathway to be working?
Sites where HMP shunt is active (organs)
Lactating mammary glands, liver, adrenal cortex, RBCs
Three differences between the nonoxidative and oxidative arms of the HMP shunt
1) The enzymes (G6PD for oxidative, transketolases for nonox), 2) B1 required for nonox (but ox is limiting), 3) Nonox is reversible, ox is irreversible
Chronic granulmatous disease is a deficiency of what enzyme?
Two common examples of catalase-positive species which may cause serious infections in pts with chronic granulomatous disease
Staph aureus and Aspergillus
Defects and genetics of essential fructosuria and fructose intolerance. Which is more serious?
Essential frucosuria - fructokinase, AR. Fructose intolerance (more serious) - aldolase B, AR.
Hypoglycemia, jaundice, cirrhosis, vomiting
Which tend to be more serious, fructose disorders or galactose disorders?
Treatment for fructose intolerance (and reasoning)
Decreased intake of fructose and sucrose (which is glucose + fructose)
Defects and genetics of galactokinase deficiency and galactosemia. Which is more serious?
Galactokinase def - galactokinase, AR. Classic galactosemia (more serious) - Galactose-1-phosphate uridyltransferase, AR
Why are fructose disorders typically less serious than galactose disorders?
Fructose can still be converted to glucose-6-phosphate (through Fructose-6-Phosphate). Galactose has no exit but galactitol (which is toxic)
Infant with cataracts, failure to track objects or develop a social smile, few other symptoms
Failure to thrive, jaundice, hepatomegaly, cataracts, MR
Treatment for classic galactosemia and reasoning behind it
Exclude galactose and lactose (galactose + glucose)
What is the main toxic substance in galactose disorders and what does it damage primarily?
Galactitol causes cataracts
The more serious fructose and galactose deficiencies lead to depletion of what?
PO4 (because they are generating phosphate-sugars which cant be metabolized)
Give the two main steps in sorbitol metabolism
Glucose to Sorbitol (by Aldose reductase). Sorbitol to Fructose (by sorbitol dehydrogenase). NADPH required for rxn 1, NAD+ required for rxn 2
What cells are missing a sorbitol related enzyme, what enzyme is it, and what is the effect?
Schwann cells, lens, retina, and kidneys are missing sorbitol dehydrogenase. Sorbitol accumulates (and has osmotic effects). Cause of numerous problems in diabetics
What is another name for lactose and what enzyme metabolizes it to what?
Galactosyl-beta-1,4-glucose. Metabolized by lactase to galactose
Essential glucogenic amino acids
Met, Val, Arg, His
Essential glucogenic/ketogenic AAs
Ile, Phe, Thr, Trp
Which two AAs are required during periods of growth? Which two AAs are in high levels in histones?
Growth - Arg and His. Histones - Arg and Lys
What enzyme is the rate limiting step in the urea cycle and what substance activates this step?
Carbamoyl phosphate synthetase 1. Activated by N-acetylglutamate
Spastic paresis of lower extremity, choreoathetoid movements
Arginase deficiency. Will see increased arginine
What donates a NH4+ group into the urea cycle
Aspartate (which converts cirtulline to argininosuccinate)
AAs with 3 titrable protons
Histidine, arginine, lysine, aspartic acid, glutamic acid, cysteine, tyrosine
Treatments for hyperammonemia
Limit protein. Benzoate or phenylbutyrate (bind AAs leading to excretion). Lactulose to acidify Gi and trap NH4 for excretion
Tremor, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
What is the most common urea cycle disorder and what is its genetics?
OTC deficiency. X recessive
OTC deficiency is X recessive. All the other urea cycle disorders are of what genetics?
Enzyme deficiencies of the urea cycle (6)
1) Carbamoyl phosphate synthase, 2) OTC (most common), 3) Argininosuccinic acid synthase, 4) Argininosuccinic acid lyase, 5) Arginase, 6) N-acetylglutamate synthase (affects activator of rate limiting step rather than a step in the urea cycle per se)
Derivatives of phenylalanine (7)
Tyrosine (yields thyroxine) --> Dopa (yields melanin) --> Dopamine --> NE --> Epi
Derivatives of tryptophan
Niacin (requires B6, generates NAD+/NADP+) and Serotonin (requires BH4, generates melatonin)
Derivatives of arginine
Creatinine, urea, No
Breakdown products via MAO and COMT
Dopamine to HVA, NE to VMA, Epi to Metanephrine
Phenylethanolamine N-methyl transferase
NE to Epi (requires SAM). Activated by cortisol
What enzyme does carbidopa inhibit?
Dopa decarboxylase (converts dopa to dopamine with help of B6)
What vitamin is required to convert dopamine to NE and what enzyme carries this out?
Dopamine B-hydroxylase with Vitamin C
Defects and genetics of PKU
Deficiency of phenylalanine hydroxylase or BH4 (tetrahydrobiopterin) cofactor. AR
What becomes essential in PKU?
Tyrosine (which is made from Phe and subsequently makes Dopa, Dopamine, NE, and Epi)
MR, growth retardation, seizures, fair skin, eczema, musty body odor
When do you screen for PKU
2-3 days after birth
Microcephaly, MR, growth retardation, congenital heart defects
Defect and genetics of alkaptonuria (ochronosis)
Homogentistic acid oxidase deficiency. AR
Dark connective tissue, brown pigmented sclera, debilitating arthralgias (sometimes) but often asymptomatic.
Alkaptonuria. Urine will turn black on prolonged exposure to air
Defects and genetics of albinism
Tyrosinase defect (AR) or defective tyrosine transporters (variable inheritence). Can also result from lack of migration of neural crest cells
Defects and genetics of homocystinuria
AR. One of three defects: 1) Cystathionine synthase defect, 2) Decreased affinity of cystathionine synthase for pyridoxal phosphate (give B6), 3) Homocysteine methyltransferase def (give B12)
What becomes essential in homocystinuria?
Mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation, atherosclerosis, renal infarcts
Homocystinuria (will also find high levels of homocysteine in urine)
Defect and genetics in cystinuria
AR. Defect in renal tubular transporter for cysteine, ornithine, lysine, and arginine (PCT)
Treatment for cystinuria
Acetazolamide to alkalinize urine
Defect in maple syrup urine disease
Blocked degradation of branched AAs (isoleucine, leucine, valine) due to decreased alpha-ketoacid dehydrogenase
What should you give in maple syrup disease and why?
Thiamine. Alpha-ketoacid dehydrogenase (which is deficient) requires B1, B2, B3, B5 and Lipoic Acid
Severe CNS defects, MR, death, strange smell to urine
Maple syrup disease
Defect and genetics of hartnup disease
AR. Defective neutral AA transporter on renal and intestinal epithelial cells. Will see tryptophan in urine
Hartnup disease leads to a condition very similar to what vitamin deficiency?
Pellagra (Vit B3 deficiency)
What is the effector for insulin, glucagon, and epi effects on glycogen metabolism in liver and muscle
cAMP --> PKA. PKA phosphorylates glycogen phosphorylase kinase, activating it
In glycogen, what is the bond at branches? What is the bond at linkages?
Branches - alpha 1,6. Linkages - alpha 1,4.
Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, hepatomegaly, increased uric acid
Von Gierkes disease (type 1). Deficiency of glucose-6-phosphatase
Cardiomegaly and early death
Pompes disease (type 2) infantile form. Deficiency of lysosomal alpha 1,4 glucosidase (acid maltase). Is the only glycogen storage disease that is also lysosomal
Diaphragm weakness, respiratory failure in an adult
Pompes disease adult form (type 2 glycogen storage). Deficiency of lysosomal alpha 1,4 glucosidase
What is the presentation of Cori disease and what is the enzyme deficiency?
Similar to Von Gierkes but with normal blood lactate (gluconeogenesis is intact). Debranching enzyme (alpha 1,6 glucosidase) deficiency
Painful muscle cramps, myoglobinuria with exercise
McArdles disease. Deficiency in skeletal muscle glycogen phosphorylase
Peripheral neuropathy of hands and feet, angiokeratomas, cardiovascular and renal disease
Fabrys disease. Deficiency of alpha galactosidase A
Defect and genetics of Fabrys disease
X recessive. Deficient alpha galactosidase A leads to accumulation of ceramide trihexosidase. Mainly affects fibroblasts
Hepatosplenomegaly, aseptic necrosis of femur, bone crises, abnormal looking macrophages
Gauchers disease. Most common lysosomal storage disease
Defect and genetics of Gauchers
Autosomal recessive. Deficiency of glucocerebrosidase leading to glucocerebroside accumulation
Progressive neurodegeneration, hepatosplenomegaly, cherry red spot on macula, foam cells
Defect and genetics of Niemann-Pick
Autosomal recessive. Sphingomyelinase deficiency
Progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, no hepatosplenomegaly
Defect and genetics of Tay Sachs
AR. Defective hexosaminidase A leads to GM2 ganglioside accumulation
How do you differentiate Tay-Sachs from Niemann-Pick?
Hepatosplenomegaly in Niemann-Pick, none in Tay-Sachs
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Defect and genetics in Krabbes disease
AR. Galactocerebrosidase deficiency
Central and peripheral demyelination with ataxia and dementia
Defect and genetics in metachromatic leukodystrophy
AR. Deficiency of arylsulfatase A leads to accumulation of cerebroside sulfate
Developmental delay, airway obstruction, corneal clouding, hepatosplenomegaly
Hurlers syndrome. Will also have gargoylism
Defect and genetics of Hurlers
AR. Alpha-L-iduronidase deficiency leads to accumulation of heparan sulfate and dermatan sulfate
Mild developmental delay, airway obstruction, hepatosplenomegaly, aggressive behavior
Defect and genetics in Hunters
X recessive. Iduronate sulfatase leads to accumulation of heparan sulfate and dermatan sulfate (same substances that build up in Hurlers)
Weakness, hypotonia, hypoketotic hypoglycemia
High dicarboxylic acids, low glucose and ketones
Acyl-CoA dehydrogenase deficiency (cant breakdown FAs in mitochondria)
Glycerol from triglycerides is degraded to what by what and where (organ)?
To DHAP by Glycerol Kinase in the liver. DHAP can then undergo glycolysis or gluconeogenesis
What esterifies most plasma cholesterol?
What degrades triglycerides in IDL and in adipocytes respectively?
IDL - Hepatic Lipase (HL). Adipocytes - Hormone-sensitive lipase. Otherwise TGs degraded by LPL (in chylomicrons and VLDL)
What transfers cholesterol esters to lipoprotein particles?
Give the major function of each of the following apolipoproteins: E, A-1, C-2, B-48, and B-100
E - mediates remnant uptake, A-1 activates LCAT, C-2 is a LPL cofactor, B-48 chylomicron secretion, B-100 binds LDL receptor (extrahepatic uptake)
Where is HDL secreted from?
Liver and intestine
Defect in type 1 familial dyslipidemia
Hyperchylomicronemia due to LPL deficiency or altered Apo C-2. Pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas (no increased risk of atherosclerosis)
Defect in IIa familial hypercholesterolemia
Absent or reduced LDL receptors. AD. Accelereated atherosclerosis, tendon xanthomas, corneal arcus
Defect in type IV familial dyslipidemia
Hepatic overproduction of VLDL. Pancreatitis
Defect and genetics of abetalipoproteinemia
Failure to synthesize lipoproteins due to deficiencies in apoB-100 and apoB-48. AR
Failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness
What acid base disorder do people with bulemia get and what is the major complication?
Metabolic alkalosis. High risk for arrhythmias with met alk
What is it called when you hear a crunch sound on lung auscultation, what causes it, and what condition often leads to it?
Hemimans crunch, usually secondary to Boerhaves syndrome (rupture esophagus due to wretching). Often associated with bulimia
If you can get them food, which child is more likely to die, one with kwashiorkor or one with marasmus?
The one with kwashiorkor. It has been wreaking havoc on their liver
Child with edema, flaky dermatitis, reddish hair, copper deficiency
If a nonsmoker gets squamous metaplasia in the lung, what might have caused this?
Vitamin A deficiency
What should you associate with eating bear liver?
Hypervitaminosis A - cerebral edema, papilledema, headache
What two organs is hypervitaminosis A most toxic to?
Brain and liver
Where does PTH act to affect calcium reabsorption in the kidney?
The distal tubule (where thiazides act)
Where does PTH act to affect phosphorus reabsorption in the kidney?
It decreases phosphorus reabsorption in the proximal tubule. It also decreases bicarb reabsorption here too
What is the only hormone with a receptor on osteoclasts?
What is released when Vitamin D and PTH respectively bind to osteoblasts?
Vitamin D - alk phos (associated with bone growth), PTH - IL-1 (osteoclast activating factor)
Why would a patient on phenytoin get hypocalcemia?
CYP450 system metabolizes Vitamin D. Phenytoin induces this system
What enzyme is increased by drugs that induce the CYP450 system?
Two things you see in kids with rickets that you dont see in adults with osteomalacia
Soft skulls and Ricketic rosaries (bumps around ribs)
Most common complication of hypervitaminosis D
What vitamin deficiency is associated with hemolytic anemia?
What is the most significant complication of hypervitaminosis E and why?
Anticoagulation. Inhibits synthesis of Vitamin K dependent factors. Be especially careful if the patient is on warfarin as these will have synergistic effects
Why are newborns usually deficient in vitamin K?
They have about a 3 day supply from mom. Otherwise, we get most Vitamin K from bacteria in our gut, and they havent been colonized yet
Main window for hemorrhagic disease of the newborn
Days 3 to 5 (maternal supplies last until day 3, and bacteria colonize by day 5)
What converts Vitamin K to the active form?
Epoxide reductase (usually in bacteria)
What does vitamin K do to vitamin K dependent clotting factors and how does that allow them to work?
Gamma carboxylates their glutamic acid residues. This allows them to bind Ca which they use to bind to clots
Most common causes of vitamin K deficiency
Antibiotics, being a newborn, malabsorption, warfarin
Hemorrhage around hair follicules, cork screw hair, glossitis, kelosis around ankles, hemorrhagic diathesis
Most common complication of hypervitaminosis C
Renal stones (uric acid, others as well)
Most common palsies seen in dry beriberi
Common peroneal (foot drop), Radial (wrist drop), Ulnar (claw hand)
What should you give a patient before you give them glucose?
Thiamine (to prevent wernickes)
What condition often presents with a necklace configuration dermatitis?
Pellagra (along with dementia and diarrhea)
Which vitamin is needed for heme synthesis and what is its role?
B6, it is a cofactor for the first reaction (ALA synthase)
How are AST and ALT relevant to starvation?
Transamination (they are transaminases) are needed to convert AAs (for example from muscle) such as alanine to substrates that can be used for gluconeogenesis
What two AAs can be transaminated to make substrates for gluconeogenesis and what substrates do they make respectively?
Alanine can be made into pyruvate, Aspartate can be made into oxaloacetate
Most common cause of B6 deficiency
Is Biotin more related to glycolysis or gluconeogenesis
Gluconeogenesis. It is a cofactor for pyruvate decarboxylase (which turns pyruvate to OAA, allowing the option of gluconeogenesis)
Alopecia with a rash in a patient consuming lots of raw eggs
What does chromium do in the body?
Helps insulin do its job
What does copper do in the body?
Plays a role in lysl oxidase (crossbridging of collagen fibrils and elastic tissue). Deficiency leads to red hair and dissecting aortic aneurysm
What role does selenium play in the body?
Cofactor in HMP shunt (glutathione peroxidase reaction)