Biochemistry Flashcards
What is the only histone that is not located in the nucleosome core?
H1
what is the form of chromatin that is transcriptionally active?
Euchromatin
What are the purine nucleotides?
What are the pyrimidine nucleotides?
Purines - A, G
Pyrimidines - C, U, T
How can you make uracil from cytosine?
Deamination of cytosine makes uracil
What are the amino aids necessary fro purine synthesis?
GAG
Glycine
Aspartate
Glutamine
you also need tetrahydrofolate
what is the rate limiting enzyme in pyrimidine base production?
Carbamoyl phosphate synthetase II
What enzyme does Hydroxyurea block that’s used in the synthesis of pyrimidines?
Hydroxyurea blocks ribonucleotide reductase
Used to treat sickle cell disease and cancer
What enzyme does 5-FU block that’s used in the synthesis of pyrimidines?
Thymidylate synthase is blocked therefore you can’t make dTMP
What enzyme does MTX/TMP block that’s used in the synthesis of pyrimidines?
Dihydrofolate reductase is blocked therefore you can’t make dTMP
What enzyme does 6-MP block that’s used in the synthesis of purines?
6-MP inhibits glutamine PRPP Amidotransferase
Note that this is the rate limiting enzyme in purine synthesis
What enzyme does Mycophenolate block that’s used in the synthesis of purines?
Mycophenolate blocks IMP dehydrogenase so you can’t make GMP
Autosomal recessive disease where you are unable to convert orotic acid to UMP because of defect in UMP synthase
Orotic aciduria
effects de novo pyrimidine synthesis pathway
Patient presents with megaloblastic anemia that does NOT improve with administration of vitamin B12 or folic acid, failure to thrive and they do NOT have hyperammonemia. The patient has increased orotic acid in the urine
Orotic aciduria
What is the treatment for orotic aciduria
Oral uridine administration
What two drugs inhibit xanthine oxidase?
Allopurinol and Febuxostat
What immunosuppressants do you need to decrease when you are also giving a patient allopurinol or febuxostat?
Azathioprine and 6-MP
What is the triad seen in SCID?
- severe recurrent infections
- chronic diarrhea
- failure to thrive
Excess ATP and dATP imbalances nucleotide pool via feedback inhibition of ribonucleotide reductase therefore preventing DNA synthesis and therefore decreasing lymphocyte count
Adenosine deaminase deficiency
leads to SCID, AR disease
Patient presents with excess uric acid production and de novo purine synthesis. They have a defective purine salvage pathway because they do not have HGPRT
Lesch nyhan syndrome
HGPRT converts hypoxanthing to IMP
A patient is found with retardation, self-mutilation, aggression, hyperuricemia, gout, and choreoathetosis
Lesch-Nyhan syndrome
What can you use to treat lesch-nyhan syndrome?
Allopurinol, but note that this will not help with CNS problems
a point mutation in DNA where it results in the same amino acid, often the third base has changed (tRNA wobble)
Silent mutation
A point mutation where there has been a change in the amino acid but it’s conservative because the new amino acid is similar in chemical structure but the result is a polypeptide product that has different structural or functional properties
missense mutation
Ex - sickle cell
A point mutation that results in an early stop codon
Nonsense mutation
A point mutation that results in misreading of all nucleotides downstream, often resulting in a truncated, nonfunctional protein
Frameshift mutation
What autoantibody is made against topoisomerase?
anti-Scl-70
seen in diffuse scleroderma
mutation in nucleotide excision repaid resulting in lack of repair of pyrimidine dimers due to UV light exposure
————children of the night
Xeroderma Pigmentosum (AR)
what is the repair mechanism where newly synthesized strand is recognized and mismatched nucleotides (like a T with a G) are removed and gap is filled and resealed?
Mismatch Repair
In what cancer is mismatch repair mutated?
hereditary nonpolyposis colorectal cancer
a patient presents with decreased IgA, cerebellar ataxia, poor smooth pursuit of the eyes and they are sensitive to ionizing radiation. the patient has a mutated nonhomologous end joining
Ataxia telangiectasia
What is the mRNA start codon?
AUG
methionine in eukaryotes
formylmethionine (f-met) in prokaryotes
What are the 3 mRNA stop codons?
UGA
UAA
UAG
how many RNA polymerases do prokaryotes have and what do they do?
Prokaryotes have 1 RNA polymerase that makes rRNA, mRNA and tRNA
What antibiotic inhibits prokaryote RNA polymerase?
Rifampin
What are the RNA polymerases used in eukaryotes and what do they make?
RNA polymerase 1 - makes rRNA
2- makes mRNA
3- makes tRNA
a patient eats a amanita phalloides death cap mushroom and gets severe hepatotoxicity. What is the toxin and what is it inhibiting?
Alpha amanitin is the toxin and it inhibits RNA polymerase II
Where does RNA processing occur and what are the 3 stages of RNA processing?
Occurs in the nucleus
- capping on 5’ end (addition of 7-methylguanosine cap via SAM)
- polyadenylation on 3’ end, signal is AAuAAA
- splicing out introns
what sequence sits at the 3’ end of tRNA?
CCA
what antibiotic binds to the 30S subunit preventing attachment of aminoacyl-tRNA from entering the acceptor site?
Tetracyclines
what enzyme is responsible for adding an amino acid to the tRNA?
aminoacyl-tRNA synthetase
What antibiotics bind to 30S and inhibit formation of initiation complex and causes misreading of mRNA
Aminoglycosides
What antibiotics binds the 50s subunit and inhibits peptidyl transferase? (23s rRNA)
Chloramphenicol
what antibiotics bind to the 50s subunit and prevent release of uncharged tRNA after it has donated its amino acid, thereby preventing the translocation step?
Macrolides
what tumor suppressors prevent the G1 to S phase progression?
Rb and p53
What are the Cyclin/CDK involved in G1 to S phase?
Cyclin D with CDK4 and Cyclin E with CDK2
What are the cyclin/CDK involved in the G2 to M phase?
Cyclin A with CDK2 and Cyclin B with CDK1
what are the functions of smooth ER?
- steroid synthesis
2. detoxification of drugs and poisons
What is responsible for synthesizing enzymes like ChAT and peptide neurotransmitters in neurons?
Nissl bodies or RER found only in dendrites
What must be added to a protein in order for it to go to the lysosome?
Mannose-6-phosphate
A patient is deficient in a phosphotransferase and is unable to add mannose-6-phosphate to proteins. what is the disease and what’s the result?
The patient has I cell disease
This results in enzymes being secreted outside the cell instead of being targeted to the lysosome
A patient presents with coarse facial features, clouded corneas, restricted joint movement and high plasma levels of lysosomal enzymes. what is this?
I cell disease
often fatal in childhood
Name 5 drugs that act on microtubules
- Mebendazole
- Griseofulvin
- Vincristine/Vinblastine
- Paclitaxel
- Colchicine
What are the two molecular motor proteins that transport cellular cargo toward opposite ends of microtubule tracts?
Dynein - retrograde to microtubule (+ –> -)
Kinesin - anterograde to microtubule (- –> +)
a patient presents with recurrent pyrogenic infections, partial albinism, and peripheral neuropathy. What is the syndrome and what is mutated?
Chediak higashi syndrome
Mutated lysosomal trafficking regulator gene (LYST)
A patient presents with decreased fertility, bronchiectasis, and recurrent sinusitis what is the syndrome and what is the defect?
The patient has Kartagener’s syndrome (primary ciliary dyskinesia)
They have immotile cilia due to a dynein arm defect - associated with situs inversus
What cell type is seen with a vimentin stain?
Connective tissue
Sarcomas
What cell type is seen with a desmin stain?
Muscle
rhabdo or leiomyoscaroma
What cell type is seen with a cytokeratin stain
Epithelial cells
Carcinoma
What cell type is seen with a GFAP stain?
Neurogluia
Astrocytoma, glioblastoma
What cell type is seen with a neurofilament stain?
Neurons
Neuroblastoma, primitive neuroectodermal tumor
what drug inhibits the Na/K ATPase pump by binding to the K+ site?
Ouabain
What is the mnemonic to remember collagen types 1 - 4?
Strong (1), Slippery (2), Bloody (3), Bowel Movement (4)
Where is type 1 collagen found
bone, skin, tendon, dentin, fascia, cornea, late wound repair
Where is type 2 collagen found
Cartilage (including hyaline), vitreous body, nucleus pulposus
where is type 3 collagen found
Reticulin - skin, blood vessels, uterus, fetal tissue, granulation tissue
where is type 4 collagen found
Basement membrane or basal lamina
A patient is deficient in vitamin C and they are DX with scurvy, what exactly can they not do?
the step of collagen synthesis with hydroxylation of specific proline and lysine residues
if a patient can’t form a triple helix during the glycosylation step of collagen synthesis, what disorder do they most likely have?
Osteogenesis imperfecta
If a patient is unable to perform the cross linking step in collagen synthesis to make collagen fibrils, what disorder do they most likely have?
Ehlers danlos
A patient presents with multiple fractures with minimal trauma, blue sclerae (transluscent CT over the choroidal veins), hearing loss and dental imperfections (lack of dentin). What is the name of the disorder and the defect
Osteogenesis imperfecta. Defect in type 1 collagen. the most common form is AD and is due to decreased production of otherwise normal type 1 collagen
A patient presents with hyperextensible skin, tendency to bleed and hypermobile joints
Type 1 or 5 collagen most frequently
Ehlers danlos
A patient presents with hematuria, oliguria, high frequency hearing loss - what’s wrong with him?
Alport syndrome
Defect in Type 4 collagen - basement membranes
a patient presents with hyperelastic joints, problems wit heart vales, aorta, very tall, arachnodactyly, pectus carinatum and Steinberg sign. What is the syndrome and defect?
Marfan syndrome - fibrillin defect
Why do we get wrinkly?
reduced collagen and elastin production
What is the blotting procedure where you use a known DNA probe to ID a DNA sample?
Southern blotting
What is the blotting procedure where you use a known DNA probe with an RNA sample. This is useful for studying mRNA levels
Northern blot
What is the blotting procedure where you use an Ab probe to look at a protein sample
Western blot
What is the blotting procedure where you use a labeled oligonucleotide probe to look at DNA binding proteins like transcription factors
Southwestern blot
What type of ELISA uses a test antigen to see if a specific antibody is present in a person’s blood?
Indirect ELISA
What type of ELISA uses a test antibody to see if a specific antigen is in a patients blood?
Direct ELISA
What technique should you use is you want to look for specific localization of genes and direct visualization of anomalies at the molecular level?
FISH
What is the genetic term where the phenotype varies among individuals with the same genotype. Example: 2 patients with neurofibromatosis type 1 may have varying disease severity.
Variable expressivity
What is the genetic term where not all individuals with a mutant genotype shows the mutant phenotype. Example: may skip a generation, BRCA1 gene mutation doesn’t always result in breast or ovarian cancer?
Incomplete penetrance
what is the genetic term where one gene contributes to multiple phenotypic effects? Example: PKU causes many seeminly unrelated symptoms ranging from mental retardation to hair/skin changes
Pleiotropy
What is the genetic term where differences in gene expression depend on whether the allele is of maternal or paternal origin
Imprinting
What is the genetic term where there is increased severity or earlier onset of disease in succeeding generations?
Anticipation
What is the genetic term where if a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is NOT true of oncogenes.
Loss of heterozygosity
“two hit hypothesis”
What is the genetic term that exerts a dominant effect where a heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning. Example: mutation of a transcription factor in its allosteric site. Nonfunctioning mutant can still bind DNA, preventing wild type transcription factor from binding.
Dominant negative mutation
What is the genetic term where there’s a tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations?
Linkage disequilibrium
What is the genetic term that occurs when cells in the body differ in genetic makeup due to postfertilization loss or change of genetic information during mitosis.
Mosaicism
What is the genetic term where mutations at different loci can produce the same phenotype? Examples include how mafran’s syndrome, MEN 2B, and homocystinuria all cause marfanoid habitus. or all the different things that can cause albinism
Locus heterogeneity
What is the genetic term where there’s the presence of both normal and mutated mitochondrial DNA, resulting in variable expression in mitochondrial inherited disease?
Heteroplasmy
A patient presents with mental retardation, hyperphagia, obesity, hypogonadism and hypotonia. They also have a chromosome 15 problem where the mom gene is inactivated and the dad gene is deleted.
Prader-willi syndrome
A patient presents with mental retardation, seizures, ataxia, and inappropriate laugher. They also have a chromosome 15 problem where the dad gene is inactivated and the mom gene is deleted
Angelman’s syndrome
A patient presents with dwarfism, short limbs, larger head, but trunk size is normal. They have a super old dad. Whats the disorder, the inheritance pattern and the defect?
Achondroplasia, AD, defect of fibroblast growth factor receptor 3
a patient presents with a colon covered with adenomatous polyps after puberty. What is the disease, inheritance pattern and the defect?
Familial adenomatous polyposis. This is due to a mutation on chromosome 5, APC gene
The concern is that it progresses to colon cancer unless colon is resected
a patient presents with bilateral massive enlarged kidneys. They have flank pain, hematuria, hypertension, and progressive renal failure. What is the disease, inheritance pattern and the defect?
Autosomal dominant polycystic kidney disease
The defect is on chromosome 16, PKD1 gene
A patient presents with elevated LDL due to defective or absent LDL receptor. They have severe atherosclerotic disease early in life, tendon xanthomas and they may have an MI very early in life. What is the disease, inheritance pattern and the defect?
Familial hypercholesterolemia (Hyperlipidemia type IIA) Autosomal dominant
A patient presents with telangiectasia, recurrent epistaxis, skin discolorations and arteriovenous malformations. What is the disease, inheritance pattern and the defect?
This is Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - AD
This is a inherited disorder of blood vessels
A patient presents with hemolytic anemia, increased MCHC, increased viscosity in blood, jaundice, worsened with viral infections and abnormal osmotic fragility test. What is the disease, inheritance pattern and the defect?
Hereditary spherocytosis. AD. This is spheroid erythrocytes due to a spectrin or ankyrin defect.
A patient presents with depression, progressive dementia, choreiform movements, caudate atrophy, and decreased levels of GABA and ACh in the brain. What is the disease, inheritance pattern and the defect?
This is Huntington’s disease (AD), gene located on chromosome 4 it is a trinucleotide repeat (CAG)
A patient presents with café-au-lait spots, neural tumors, lisch nodules (pigmented iris hamartomas), scoliosis and optic pathway gliomas. What is the disease, inheritance pattern and the defect?
This is neurofibromatosis type 1 (von Recklinghausen’s disease) AD. defect on long arm of chromosome 17
A patient presents with tinnitus, balance problems, hearing loss due to bilateral acoustic schwannoma and juvenile cataracts. What is the disease, inheritance pattern and the defect?
This is neurofibromatosis type 2. AD
NF2 gene on chromosome 22
A patient presents with seizures, intellectual disability, and angiofibromas. they also have ash leaf spots on skin, renal cysts and renal angiomyolipomas. What is the disease, inheritance pattern and the defect?
Tuberous sclerosis - AD, mutated hamartin (tuberin) gene
shwos incomplete penetrance and variable persentation
A patient presents with hemangioblastomas or retina/cerebellum/medulla, the majority of affected individuals also develop multiple bilateral renal cell carcinomas and other tumors. What is the disease, inheritance pattern and the defect?
This is von Hippel-Lindau disease, AD. deletion of VHL gene (tumor suppressor) on chromosome 3.
results in constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors
what deletion is seen in cystic fibrosis?
CFTR gene is deleted on chromosome 7, commonly a deletion of Phe 508
this is AR
A patient presents with recurrent pulmonary infections, chronic bronchitis, bronchiectasis, pancreatic insufficiency, nasal polyps and meconium ileus as a newborn. What is wrong with them?
Cystic fibrosis
What is the inheritance and the mutation seen in Duchenne’s muscular dystrophy?
X-linked frameshift mutation, deletion of dystrophin gene
onset before age 5 yo
How do you diagnose muscular dystrophies?
Muscle biopsy and increased CPK
as the disease progresses the CPK will decreased due to inactivity and muscle loss
what is the less severe form of duchennes muscular dystrophy?
Becker’s
This is a X-linked mutated dystrophin gene
A patient presents with marcoorchidism, long face with a large jaw, large everted ears, autism, mitral valve prolapse and mental retardation.
Fragile X syndrome
X linked. CGG repeat - FMR1 gene
What is the trinucleotide repeat seen in Friedreich’s ataxia?
GAA
What is the trinucleotide repeat seen in myotonic dystrophy?
CTG - autosomal dominant
what 2 problems do you worry about with kids with Down’s syndrome?
increased risk of ALL and increased risk of Alzheimer’s disease
A patient is pregnant and their quad screen shows decreased AFP, increased beta hCG, decreased estriol and increased inhibin A, what are you worried about?
Down syndrome
A 1 year old presents with severe MR, rocker bottom feet, micrognathia (small jaw), low set ears, clenched hands, prominent occiput and congenital heart defects.
Edwards syndrome
Trisomy 18
A patient is pregnant and their quad screen shows decreased AFP, decreased beta-hCG, decreased estriol and normal inhibin A, what are you worried about?
Edwards syndrome
A patient presents with severe MR, rocker bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly and congenital heart disease. what do they have?
Patau’s syndrome - trisomy 13
what is it called when the long arms of two acrocentric chromosomes fuse at the centromere and the 2 short arms are lost?
Robertsonian translocation
A patient has cri-du-chat syndrome - where is the deletion?
microdeletion of short arm of chromosome 5
a patient has Williams syndrome - where is the deletion?
microdeletion of long arm of chromosome 7
A patient presents with elf-like facies, intellectual disability, hypercalcemia, well developed verbal skills, extreme friendliness with strangers and cardiovascular problems. what is the syndrome and why do they have hypercalcemia?
Williams syndrome
They have hypercalcemia due t increased sensitivity to vitamin D
90% of DiGeorge patients have what deletion?
Chromosome 22 q 11 deletion
A patient presents with arthralgias, fatigue, headaches, skin changes, sore throat and alopecia. what vitamin are they overloaded with?
Vitamin A - retinol
a patient presents with confusion, ophthalmoplegia, ataxia and confabulation, personality changes, memory loss that’s permanent. They are a raging alcoholic. what’s the vitamin Deficiency and what is damaged?
Thiamine deficiency leading to Wernicke-Korsakoff syndrome
Damage is to the medial dorsal nucleus of the thalamus and mammillary bodies.
What should you always give to an alcoholic or malnourished patient before you give them glucose?
Thiamine should always be given before you give glucose
A patient presents with diarrhea, dermatitis and dementia - what vitamin are they deficient in?
Niacin or Vit B3 leading to Pellagra
note patients can also have glossitis
A patient presents with convulsions, hyperirritability and peripheral neuropathy. The patient also has sideroblastic anemia what drugs did they take too much of?
Oral contraceptives and INH can lead to a deficiency of Vitamin B6 (pyridoxine)
What should a patient on INH be supplemented with?
Vitamin B 3 (niacin) and vitamin B6 (pyridoxine)
A patient presents with macrocytic megaloblastic anemia without neurological symptoms, what is the diagnosis?
Folic acid (vitamin B9) deficiency
where is vitamin B 12 absorbed in the gut?
terminal ileum
If a patient has increased methylmalonic acid and increased homocystene, what is the patient deficient in?
Vitamin B 12
If a patient has increased homocysteine but normal MMA levels, what is the patient deficient in?
Folic acid (Vitamin B 9)
What vitamin helps with iron absorption by keeping iron in the Fe2+ reduced state?
Vitamin C (ascorbic acid)
what enzyme from the kidney converts vitamin D from its stored form to its active form?
1 alpha hydroxylase
what is breast milk decreased in that you should supplement in dark-skinned patients?
Breast milk has decreased vitamin D
in what disease do you see EXCESS vitamin D, and why?
Sarcoidosis, due to increased activation of vitamin D by epithelioid macrophages
A patient presents with increased fragility of RBCS (hemolytic anemia), muscle weakness, posterior column and spinocerebellar tract demyelination leading to ataxia and peripheral neuropathy. what vitamin are they deficient in?
Vitamin E
how does vitamin K activates factors 2, 7, 9, 10, protein C and protein S?
Catalyzes gamma-carboxylation of glutamic acid residues on various proteins
what vitamin are neonates given at birth to prevent hemorrhage?
Vitamin K
neonates have a sterile gut and therefore they do not have the ability to make vitamin K
the patient would have increased PT and aPTT but normal bleeding time
a patient presents with delayed wound healing, hypogonadism, decreased adult hair (axilla, facial, pubic), dysgeusia, and anosmia. What vitamin might they be deficient in?
Zinc deficiency
what are two enzymes that require zinc?
Lactate dehydrogenase and carbonic anhydrase
Give the metabolism of ethanol…. ready… go
Ethanol to Acetaldehyde via alcohol dehydrogenase
acetaldehyde to acetate via acetaldehyde dehydrogenase
What are the limiting reagents in ethanol metabolism?
NAD+ (gets converted to NADH at each step)
What enzyme does Fomepizole block?
Fomepizole blocks alcohol dehydrogenase
can be used to treat methanol or ethylene glycol poisoning
What drug blocks acetaldehyde dehydrogenase ?
Disulfiram
What drugs have disulfiram-like reactions?
Metronidazole, certain cephalosporins, procarbazine, first generation sulfonylureas
Why do alcoholic patients end up with severe hypoglycemia?
THe liver will preferentially metabolize ethanol than do gluconeogenesis. So the liver needs to make more NAD+ so it can keep metabolizing alcohol.
It will metabolize pyruvate to lactate and oxaloacetate to malate which both reactions will regenerate NAD+ from NADH
What is kwashiorkor?
Protein malnutrition
A patient has skin lesions, edema, depigmentation of skin and hair, liver malfunction and a swollen belly. what are they malnourished in?
This is Kwashiorkor, protein malnutrition.
THe patient has liver dysfunction because they have decreased apoB100 so you get fatty liver because the triglycerides can’t leave the liver
what is Marasmus?
Energy malnutrition
A patient presents with tissue and muscle wasting, loss of subcutaneous fat and variable edema. what do they have?
Marasmus - malnutrition
What’s the rate determining enzyme of glycolysis?
Phosphofuctokinase - 1
What’s the rate determining enzyme of gluconeogenesis?
Fructose- 1, 6 bisphosphatase
What’s the rate determining enzyme of TCA cycle?
Isocitrate dehydrogenase
What’s the rate determining enzyme of Glycogen synthesis?
Glycogen synthase
What’s the rate determining enzyme of Glycogenolysis?
Glycogen phosphorylase
What’s the rate determining enzyme of HMP shunt?
Glucose-6-phosphate dehydrogenase
What’s the rate determining enzyme of de novo pyrimidine synthesis?
Carbamoyl phosphate synthestase 2
What’s the rate determining enzyme of de novo purine synthesis?
Glutamine - PRPP amidotransferase
What’s the rate determining enzyme of urea cycle?
Carbamoyl phosphate synthetase 1
What’s the rate determining enzyme of fatty acid synthesis?
Acetyl-CoA carboxylase
What’s the rate determining enzyme of fatty acid oxidation?
Carnitine acyltransferase I
What’s the rate determining enzyme of ketogenesis?
HMG-CoA synthase
What’s the rate determining enzyme of Cholesterol synthesis?
HMG-CoA reductase
how many ATP can RBCs generate per glucose molecule?
2 net ATPs since RBCs can only do anaerobic glycolysis
Where is the enzyme glucokinase found?
Liver and beta cells of the pancreas
glucokinase is induced by insulin
what two enzymes are responsible for phosphorylating glucose to glucose-6-phosphate?
Glucokinase and hexokinase
what does arsenic inhibit and why is that important?
Arsenic inhibits lipoic acid which is one of the 5 cofactors needed for the pyruvate dehydrogenase complex
What findings would you see in a patient with arsenic poisoning?
Garlic breath, vomiting, rice water stools
what are the 4 different pyruvate metabolism pathways?
- alanine aminotransferase +Vit B6 turning pyruvate into alanine to carry amino groups to the liver from muscle
- Pyruvate carboxylase + biotin to make oxaloacetate to replenish the TCA cycle or be used in gluconeogenesis
- Pyruvate dehydrogenase with B1, 2, 3, 5 and lipoic acid) to transition from glycolysis to the TCA cycle
- Lactic acid dehydrogenase + B3 for the end of anaerobic glycolysis
What aer the three irreversible enzymes used in the TCA cycle?
- citrate synthase
- isocitrate dehydrogenase
- alpha ketogluterate dehydrogenase
What drives the production of ATP in the mitochondria?
Passage of electrions making the proton gradient which is coupled to oxidative phosphorylation
Where does NADH come from?
HMP shunt
Why is NADPH important list 3 reasons?
- Synthesizing FAs and cholesterol
- generating O2 free radicals (to kill bacteria in phagocytes)
- protect RBCs from O2 free radicals
Where does the HMP shunt (pentose phosphate pathway) occur?
lactating mammary glands
liver
adrenal cortex (sites of FA or steroid synthesis)
RBCs
Patients with WBCs that can utilize H2O2 generated by invading organisms and convert it to reactive oxygen intermediates but are susceptible to catalase positive species due to their ability to neutralize their own H2O2 leaving the WBCs without ROIs for fighting infections.
Chronic granulomatous disease
what enzyme is deficient in patients with chronic granulomatous disease?
NADPH oxidase
what cells utilize the respiratory burst (oxidative burst)?
monocytes, neutrophils
what reactive oxygen intermediate used in respiratory burst to attack bacteria?
bleach or hypochlorite
What is necessary to keep glutathione reduced?
NADPH
A patient presents with non-immune intravascular hemolytic anemia after eating fava beans, sulfonamides, primaquine, and antiTB drugs, what are they deficienct in?
This all is causing oxidative stress. the patient is deficient in glucose-6-phosphate dehydrogenase
A patient has oxidized hemoglobin precipitated within RBCs, what is this and what is she deficient in?
These are Heinz bodies. the patient has G6PD deficiency
When do you see Bite cells?
Bite cells result from the phagocytic removal of Heinz bodies by splenic macrophages
This is seen in GCPD deficiency
What’s the big deal with G6PD?
G6PD is used to regenerate NADH which is a reducing agent which is used by glutathione reductase to keep glutathione reduced Reduced glutathione (2 GSH) is an important antioxidant in RBCs!!
A patient presents with an AR defect and they have increased fructose in their urine and blood. What is the disorder, defect and why aer there not severe symptoms?
This patient has essential fructosuria
This is a defect in fructokinase.
Fructose builds up but it isn’t trapped in cells, so it just spills over into the urine
A patient presents with an AR defect with hypoglycemia, jaundice, cirrhosis, and vomiting. Their symptoms are much worse after they eat fructose or sucrose. What is the disorder and the defect?
This patient has fructose intolerance due to a deficiency of aldolase B
This causes fructose-1-phosphate to accumulate leading to a decrease in available phosphate which results in inhibition of glycogenolysis and gluconeogenesis.
so you use up all the phosphate because it’s all bound to fructose
what is the treatment of fructose intolerance?
decrease intake of both fructose and sucrose (glucose + fructose)
A patient presents with galactokinase deficiency - what do you expect to see?
This deficiency causes glactitol accumulation if galactose is present in the diet. it’s relatively mild. AR
Galactose will appear in blood and urine, you can have infantile cataracts - may initially present as failure to track objects or to develop a social smile
A patient is diagnosed with classic galactosemia, what enzyme is deficient?
Galactose-1-phsophate uridyltransferase
serious defects can lead to PO4 depletion
A patient presents with an AR disorder with failure to thrive, jaundice, hepatomegaly, infantile cataracts, and mental retardation.
Classic galactosemia
What is the treatment for classic galactosemia?
Exclude galactose and lactose (galactose + glucose) from diet
in classic galactosemia, what accumulates in the eye?
galactitol accumulates in the lens of the eye
what is an alternative method of trapping glucose in the cell that converts it to its alcohol counterpart?
Sorbitol via aldose reductase
What enzyme does the liver, lens of the eye, ovaries and seminal vesicles have that other cells don’t?
Sorbitol dehydrogenase, which converts sorbitol into fructose
Which cells only have aldose reductase?
schwann cells, retina and kidneys have only aldose reductase so they can only make sorbitol and not fructose
what’s the problem with increased sorbitol levels?
Sorbitol accumulates intracellularly and acts as an omsole causing osmotic damage
- cataracts, teinopathy and peripheral neuropathy are seen with chronic hyperglycemia in diabetics
A patient presents with bloating, cramps and osmotic diarrhea after eating lactose - what’s wrong with them?
Lactase deficiency - due to loss of brush border enzyme, may also follow gastroenteritis
treatment is to avoid dairy products or add lactase pills to the diet.
Can a patient that is lactase deficient eat galactose?
YES! you only need to avoid lactose, the patient does not have to avoid galactose
What is the mnemonic for essential amino acids?
PVT TIM HaLL
Phe, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Leucine, Lyscine
What are the acidic amino acids?
Asp and Glu
note that these are NEGATIEVLY charged at the body’s pH
What are the basic amino acids?
Argining, lysine, histidine
Note that these are POSITIVELY charged at the body’s pH
what amino acids are used to transport ammonia?
Alanine and glutamate
A patient presents with hyperammonemia - what is the result of this?
Results in XS NH4+, which depletes alpha-ketogluterate leading to inhibition of TCA cycle
What would ammonia intoxication look like?
tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
What is the treatment for a patient with hyperammonemia?
- Limit protein in diet
- Benzoate or phenylbutyrate (both of which bind to amino acid and lead to excretion) may be given to decrease ammonia levels.
- Lactulose to acidify the GI tract and trap NH4+ for excretion
a patient presents with increased orotic acid in their blood and urine, decreased BUN, and symptoms of hyperammonemia. What is this?
Ornithine transcarbamoylase deficieny
X linked recessive. This is the most common urea cycle disorder. Interferes with the bodies ability to eliminate ammonia
what is the catecholamine synthesis and enzymes used?
- Phenylalanine to tyrosine via phenylalanine hydroxylase
- Tyrosine to Dopa via tyrosine hydroxylase
- Dopa to Dopamine via dopa decarboxylase
- Dopamine to norepinephrine via Dopamine beta-hydroxylase
- norepinephrine to epinephrine via phenylethanolamine N-methyltransferase
what enzyme is deficient in PKU?
phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor (malignant PKU)
A pt presents with MR, growth retardation, seizures, fair skin, eczema, and musty body odor - what is this?
Phenylketonuria, AR - they will be screened 2-3 d after birth once moms enzymes are no longer high
How do you treat PKU?
Decreased phenylalanine (contained in aspartame) and increased tyrosine in diet
What causes maternal PKU and what findings are seen in the infant?
Maternal PKU is caused by lack of proper dietary therapy during pregnancy
Findings in infant: microcephaly, mental retardation, growth retardation, congenital heart defects
what causes a congenital deficiency of homogentisic acid oxidase?
Alkaptonuria (ochronosis)
What is messed up in Alkaptonuria?
The patient can’t degrade tyrosine to fumarate.
AR
A patient presents with dark connective tissue, brown pirgmented sclera, and their urine turns black on prolonged exposure to air. They also may have debilitating arthralgias - what might this be?
Alkaptonuria
The arthralgia is because homogentisic acid is toxic to cartilage
what 3 things can lead to albinism?
- lack of migration of neural crest cells (no melanocytes)
Congenital deficiency of either of the following:
- tyrosinase - inability to synthesize melanin from tyrosine – AR
- Defective tyrosine transporters
Variable inheritance due to locus heterogeneity!
a patient presents with increased homocysteine in the urine, MR
The patient has homocystinnuria
What are the 3 forms (all AR) of homocystinuria and the treatments?
- Cystathionine synthase deficiency - treat by decreased methionine and increased Cys and B12 and folate in diet
- decreased affinity of cystathionine synthase for pyridoxal phosphate - treat by increasing vit B6
- deficiency in homocysteine methyltransferase - treat with vit B12
A patient presents with cystinuria - what amino acids are they unable to transport in the PCT of the kidney?
Cysteine, ornithine, lysine, and arginine
what do you have excess of in cystinuria and what does it lead to?
increased cystine in the urine can lead to precipitation of hexagonal crystals and renal staghorn calculi
How can you treat Cystinuria?
good hydration and urinary alkalinization
you can use acetazolamide to alkalinize the urine
What is cystine?
Cystine is 2 cysteines connected by a disulfide body
What is the defect in maple syrup urine disease?
Blocked degradation of branched amino acids (Isoleucine, leucine, valine) due to decreased alpha ketoacid dehydrogenase (Vit B1)
AR
What are the findings in maple syrup urine disease?
- increased alpha ketoacids in the blood (especialy leucine)
- Severe CNS defects, mental retardations and death
- urine smells like maple syrup
What is Hartnup disease?
AR disorder defective neutral amino acid transporter on renal and intestinal epithelial cells
A patient presents with tryptophan excretion in urine and decreased absorption from the gut - leads to pellagra; what is the disease?
Hartnup disease
This leads to pellagra because without tryptophan you can’t make niacin (Vit B3)
What messenger does glucagon stimulate to have it’s affect?
glucagon stimulates adenylyl cyclase therefore increasing cAMP and activating PKA
What linkages does glycogen synthase make?
Glycogen synthase makes alpha 1, 4 glycosidic linkages
what linkages does branching enzyme make?
Branching enzyme makes alpha 1, 6 glycosidic linkages
What is the mnemonic for glycogen storage diseases?
Very Poor Carbohydrate Metabolism
Von gierke's disease (type 1) Pompe's disease (type 2) Cori's disease (type 3) Mcardles disease (type 5)
A patient presents with severe fasting hypoglycemia, increased glycogen in the liver, increased blood lactate and hepatomegaly, what is the disease?
Von Gierke’s disease
A patient presents with cardiomegaly and systemic findings leading to early death what is the disease?
Pompe’s disease
Pompe’s trashes the Pump – heart, liver, muscle
A patient presents with a milder form of Von Gierke’s disease with normal blood lactate levels. what’s the disease?
Cori’s disease
A patient presents with increased glycogen in muscle, but can’t break it down, leading to painful muscle cramps, and myoglobinuria with strenuous exercise. What is the disease?
McArdles disease
A patient presents with an AR disease and they are deficient in Glucose 6 phosphatase - what is the disease?
Von Gierke’s disease
A patient presents with an AR disease and they are deficient in lysosomal alpha 1, 4 glucosidase (acid maltase). What is the disease?
Pompe’s disease
A patient presents with an AR disease and they are deficient in debranching enzyme (alpha 1, 6 glucosidase) - what is the disease?
Cori’s disease
note that gluconeogenesis is intact
A patient presents with an AR disease where they are deficient in skeletal muscle glycogen phosphorylase - what is the disease?
McArdles Disease
What are the lysosomal storage diseases that are X linked Recessive?
Hunter’s syndrome and Fabry’s disease
What are the lysosomal storage diseases that are AR?
Gaucher’s, Niemann-Pick, Tay-Sachs, Krabbe’s, Metachromatic leukodystrophy, Hurler’s
A patient is deficient in alpha galactosidase A enzyme and is accumulating ceramide trihexoside - what is their lysosomal storage disease?
Fabry’s disease
A patient is deficient in the Glucocerebrosidase enzyme and is accumulating glucocerebroside - what is their lysosomal storage disease?
Gaucher’s disease
A patient is deficient in sphingomyelinase enzyme and is accumulating sphingomyelin - what is their lysosomal storage disease?
Niemann-Pick disease
A patient presents with a deficiency in the enzyme Hexosaminidase A and is accumulating GM2 ganglioside - what is their lysosomal storage disease?
Tay Sachs disease
A patient is deficient in Galactocerebrosidase enzyme and is accumulating Galactocerebroside - what is their lysosomal storage disease?
Krabbe’s disease
A patient is deficient in the enzyme Arylsulfatase A and is accumulating Cerebroside sulfate - what is their lysosomal storage disease?
Metachromatic leukodystrophy
A patient is deficient in the enzyme alpha - L- iduronidase and is accumulating Heparan sulfate and dermatan sulfate - what is their lysosomal storage disease?
Hurler’s syndrome
A patient is deficient in the enzyme iduronate sulfatase and is accumulating heparin sulfate and dermatan sulfate - what is their lysosomal storage disease?
Hunter’s syndrome
A patient presents with peripheral neuropathy of their hands and feet, angiokeratomas, cardiovascular and renal disease - they may also have painless papules on their lower abdomen, butt and groin. What is their disease?
Fabry’s disease
A patient presents with Hepatosplenomegaly, aseptic necrosis of their femur, bone crises, anemia, thrombocytopenia, fatigue and macrophages that look like crumpled up tissue paper
Gaucher’s Disease
What are Gaucher’s cells?
Macrophages that look like crumpled tissue paper
A patient presents with progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on their macula, and foam cells. They will die by age 2-3, they have ataxia due to accumulation in cerebellum, dysarthria, dysphagia, gradual decrease in myelin function. What is their disease?
Niemann pick disease
A patient presents with progressive neurodegeneration, developmental delay, cherry-red spot on macula lysosomes with onion skin, may have vision and hearing difficulties. What is their disease?
Tay-Sachs disease
A patient presents with peripheral neuropathy, developmental delay, optic atrophy and globoid cells. What is their disease?
Krabbe’s disease
A patient presents with central and peripheral demyelination with ataxia, and dementia. What is their disease?
Metachromatic leukodystrophy
A patient presents with developmental delay, gargoylism, airway obstruction, corneal clouding and hepatosplenomegaly. What is their disease?
Hurler’s syndrome
A patient presents with mild Hurler’s and aggressive behavior, no corneal clouding. What is their disease?
Hunter’s syndrome
What is carnitine deficiency?
The inability to transport long chain FAs into the mitochondria, resulting in toxic accumulation.
causes weakness, hypotonia, and hypoketotic hypoglycemia
what is used by the CNS for energy during periods of PROLONGED starvation?
Beta-hydroxybutyrate
T or F: Urine tests for ketones like Beta-hydroxybutyrate
False - urine tests do look for ketone bodies but NOT for Beta-hydroxybutyrate - the urine tests only for acetoacetate
What conditions cause the overproduction of ketone bodies?
In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, XS NADH shunts oxaloacetate to malate
Both of these processes stall the TCA cycle which shunts glucose and FFA to the production of ketone bodies.
When a patient is starving, how long until their glycogen reserves are depleted?
1 day
what enzyme do statins block?
HMG-CoA reductase
which apoliprotein mediates remnant uptake?
Apolipoprotein E
which apoliprotein activates LCAT?
Apolipoprotein A-1
which apoliprotein functions as a lipoprotein lipase cofactor?
apolipoprotein C-11
which apoliprotein mediates chylomicron secretion (from enterocyte to lymphatic system)?
Apolipoprotein B-48
which apoliprotein binds LDL receptor which is necessary for when you leave the liver?
Apolipoprotein B-100
which lipoprotein delivers dietary TGs to peripheral tissue and delivers cholesterol to the liver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols. and is secreted by intestinal epithelial cells?
Chylomicrons
Which lipoprotein delivers hepatic TGs to peripheral tissue and is secreted by the liver?
VLDL
Which lipoprotein is formed in the degradation of VLDL and delivers triglycerides and cholesterol to the liver?
IDL
Which lipoprotein delivers hepatic cholesterol to peripheral tissues and is formed by hepatic lipase modification of IDL in the peripheral tissue. It’s also taken up by target cells via receptor-mediated endocytosis.
LDL
Which lipoprotein mediates reverse cholesterol transport from the periphery to the liver, acts as a repository for apoC and apoE (which are needed for chylomicron and VLDL metabolism) and is secreted from both the liver and the intestines?
HDL
Which familial dyslipidemia will cause an increased in chylomicrons, TG and cholesterol?
Type I - hyper-chylomicronemia
A patient presents with an AR disease with either lipoprotein lipase deficieny or altered apolipoprotein C-II. This leads to pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas. The patient has no increased risk for atherosclerosis.
Type I familial dyslipidemia - hyper-chylomicronemia
A patient presents with an AD disease with an absent or decreased LDL receptor causing accelerated atherosclerosis, tendon xanthomas and corneal arcus. What is this?
Type II familial dyslipidemia - familial hypercholesterolemia
IIa - defective LDL receptor
IIb - mutant apoB100
A patient presents with an AD disease with hepatic overproduction of VLDL causing pancreatitis. What does this patient have?
Type IV familial dyslipidemia - hyper-triglyceridemia
Which familial dyslipidemia will cause an increase in LDL and cholesterol?
Type II familial hypercholesterolemia
Which familial dyslipidemia will cause an increase in VLDL and TG?
Type IV - hyper-triglyceridemia
what lipoproteins are a patient deficient in with Abetalipoproteinemia?
B48 and B100 are deficient which leads to decreased chylomicron and VLDL synthesis and secretion
treating with Vitamin E helps to restore some of the lipoproteins
A patient presents with an AR disease with a mutation in microsomal triglyceride transfer protein (MTP) - what is this?
Abetalipoproteinemia
What symptoms are seen in Abetalipoproteinemia?
failure to thrive, steatorrhea, acanthocytosis (spikes on RBCs), ataxia and night blindness.
A patient presents with increased chylomicron remnants, increased VLDL and increased total cholesterol - what are they deficient in?
ApoE - this is a type III familial dysbetalipidemia
What is the defect in achondroplasia?
constitutive activation of FGF3 (cell signaling receptor)
it isn’t inactivated, its OVERLY activated!
