1
Q
G protein-couple receptors
- What do they bind?
- What are the domains which make them up? (3)
A
- Bind glycoprotein hormones (eg TSH, LH, FSH)
- 3 major domains: Extacellular domain, transmembrane domain, intracellular domain
2
Q
Describe the functions of each of the (3) domains of G protein-coupled receptors.
Describe composition of the transmembrane domain in detail.
A
- Extracellular domain- responsible for ligand binding
- Intracellular domain- coupled with heterotrimeric G proteins
- Transmembrane domain- composed of nonpolar, hydrophobic amino acids (alanine, valine, leucine, etc.), arranged in an alpha-helical fashion. Serve to anchor the proteinto the phospholipid bilayer. May also play role in cellular signaling and transport.
3
Q
Maturity-onset Diabetes of the Young
- Presentation
- What is the main pathogenesis? Describe in detail
- Potential Consequences
A
- MIld, nonprogressive hyperglycemia that often worsens with pregnancy-induced insulin resistance
- Often a result of mutation of the glucokinase gene. Glucokinase = glucose sensor. Mutation leads to dec. beta cell metabolism of glucose, less ATP formation, and dec. insulin secretion
- Could lead to fetal growth retardation and sever hyperglycemia at birth
4
Q
List the (6) steps for Ggucose-induced insulin release from beta cells
A
- Glucose enters the beta cell through GLUT-2
- Glucose is metabolized by glucokinase to glucose-6-phosphate
- Glucose 6-phosphate is further metabolized by glycolysis and the Krebs cycle to produce ATP
- High ATP to ADP ratio causes closure of ATP-sensitive K+ channels
- Subsequently, depolarization of beta cells results in opening of voltage-dependent Ca2+ channels
- High intracellular Ca2+ leads to insulin release
5
Q
Hexokinase vs Glucokinase
- Location
- Affinity vs Capacity?
- Induced by insulin?
- Mutation assc. with Maturity-onset diabetes of the young?
A
- H: Everywhere but liver and pancreatic B cells; G: Liver and pancreatic B cells
- H: High affinity, low capicity; G: low affinity, high capacity
- H: Not induced by insulin; G: induced by insulin
- H: Not assc. with MODY; G: Assc. w/ MODY
6
Q
Name the Glycogen Storage Diseases
A
Very Poor Carbohydrate Metabolism
- Von Gierke Disease
- Pompe Disease
- Cori Disease
- McArdle Disease
7
Q
Describe Pompe Disease
- Deficient enzyme?
- Pathology
- Presentation
A
- Acid a-glucosidase
- Acid a-glucosidase is responsible for breakdown of glycogen w/in lysosomes. Its absence leads to glycogen accumulation w/in liver and muscle lysosomes
- Presentation: Pompe trashes the Pump (heart, liver, and muscle) – cardiomegally, hypertrophic cardiomyopathy, excercise intolerance, hypotonia, etc.
8
Q
Describe Von Gierke Dz
- Deficient enzyme
- Presentation
- Tx
A
Type I Glycogen Storage Dz
- Glucose 6- phosphatase
- Severe fasting hypoglycemia (can’t convert G6P to glucose); hepatomegaly
- Tx: frequent oral glcose/cornstarch; avoidance of fructose and galactose
9
Q
Describe Cori Dz
- Deficient enzyme
- Which other GSD is it similar to?
A
- Debranching enzyme
- It is a milder version of Von Gierke (type I)
10
Q
McArdle dz
- Deficient enzyme
- Path
- Presentation
A
- Skeletal muscle glycogen phosphorylase
- Muscles can’t breakdown glycogen in muscle (McArdle = Muscle)
- Present with painful muscle cramps, myoglobinuria w/ strenuous excercise, and arhytmia from electrolye abnormalities.
11
Q
Ehlers-Danlos syndrome
- What is it?
- Usual cause?
- Presentation
A
- Group of rare hereditary disorders charcterized by defective collagen synthesis
- The result of procollagen peptidase deficiency, which results in impaired cleavage of terminal propeptides in the extracellular space
- Patients present with joint laxity, hyperextensible skin, and tissue fragility, due to collagen which does not crosslink
12
Q
Amatoxins
- Where are they found?
- What is there MOA?
A
- Found ina variety of posionous mushrooms
- Potent inhibitors of RNA pol, thus halting mRNA synthesis
13
Q
Key presentation for cyanide poisoning
Key tx? What is its MOA?
A
- Presentation: Reddish skin discoloration, tachypnea, HA. Lab studies indicate severe lactic acidosis and dec. venous-arterial PO2 gradient
- Inhalation of inhaled amyl nitrite oxidizes ferrous iron (Fe2+) present in hemoglobin to ferric iron (Fe3+), generating methemoglobin. Methemoglobin is incapable of carrying O2 but has a high affinity of cyanide, sequestering it.
14
Q
How does hypothermia lead to a left shift of the O2-dissociation curve?
A
Decreased temps help stabilize the bonds between O2 and hemoglobin
15
Q
Fibrate medications
- Function
- MOA
- AE
A
- Dec. LDL and TG; Inc. HDL
- MOA: Upregulate LPL, resulting in inc. oxidation of fatty acids; also, inhibit cholesterol 7a-hydroxylase, which catalyzes rate-limiting step of bile acid synthesis
- Reduced bile acid production results in dec. cholesterol solubility, favoring cholesterol stone formation
16
Q
- Propionyl CoA is derived from what?
- What enzyme is responsible for its conversion to methylmalonyl CoA?
- What would deficiency of this enzyme lead to?
A
- It is derived from amino acids (Val, Ile, Met, and Thr), as well as odd-numbered fatty acids and cholesterol side chains
- Propionyl CoA carboxylase is the enzyme responsible
- Deficient enzyme leads to development of proprionic acidemia
17
Q
What is the stabilizing force for the secondary structure of proteins?
A
Hydrogen bonds
18
Q
Maple Syrup Urine Disease
- Pathogenesis
- Sx
- Dx
- Tx
5.
A
- Blocked degradation of branched amino acids– Isoleucine, Leucine, and Valine (I Love Vermont) due to decreased a-ketoacid dehydrogenase
- Sx: severe CNS defect, intellectual disabiity, and death
- Urine smells like maple syrup/ burnt sugar
- Tx: restriction from branched amino acids in diet, and thiamine supplementation
19
Q
Name the a-ketoglutarate dehydrogenase co-enzymes which may be defective in Maple Syrup Urine Dz (MSUD)
A
Tender Loving Care For Nancy
Thiamine pyrophosphate
Lipoate
Coenzyme A
FAD
NAD
20
Q
- Tetrahydrobiopterin (BH4), serves as cofactor for which enzymes?
- What enzyme is responsible for forming BH4?
- What effect would a deficiency in BH4 have?
A
- Important cofactor for the Phenylalanine hydroxylase and Tyrosine hydroxylase
- Dihydropteridine reductase is responsible for converting BH2 to BH4
- Deficiency would lead to inc. phenylalanine (can be corrected by diet) and def in tyrosine conversion to its downstream products such as dopamine, NE, Epi, and serotonin (leading to neuro deterioration)
21
Q
What antibodies have a high specificity for Rhematoid arthritis?
A
Antibodies to citrullinated peptides/ proteins (anti-CCP)
22
Q
What is the role of Small nuclear RNA (snRNA)?
What is the name of autoantibodies which work against the function of snRNA and what dz are they associated with?
A
snRNA is synthesized by RNA pol II and complexes w/ specific proteins to form small nuclear ribonucleoproteins (snRNPs). These snRNPs are essential components fo the spliceosome and remove introns from to form mature mRNA.
Autoantibodies directed against snRNPs are called anti-Smith antibodies, and are assc. with SLE.
23
Q
Metabolism of 1g of protein or carbohydrate, produces ______ Calories of energy.
Metabolism of 1g of fat produces _____ Calories of energy.
A
P/C: 4 C
F: 9 C
24
Q
Hartnup Dz
- Path
- Sx
- Possible Consequences
- Tx
A
- Defective intestinal and renal tubular absorption of dietary tryptophan. This can result in Niacin deficiency, as Niacin is synthesized from tryptophan
- Sx: Often asymptomatic but may result in photosensitvity or pellegra-like skin rashes
- Tx w/ nicotinic acid/ nicotinamide and a high-protein diet
25
What is the effect of G6PD deficiency?
What other enzyme deficiency might paint a similar picture?
_G6PD_ deficiency is a defect in the HMP shunt (aka the Pentose Phosphate Pathway), which leads to impairment of glutathione reduction due to failure to produce NADPH
**Glutathione reductase deficiency** causes a similar clinical picture
26
_Niemann-Pick Dz_
1. What type of dz is this?
2. Deficient enzyme
3. Inheritance
4. Presentation
1. LSD
2. **Sphingomyelinase**
3. AR (common in Ashkenazi Jew population)
4. Sphingomyelin accumulation, leading to _hepatosplenomegally_ , "Cherry-red" spot on macula, and _progressive neurodegeneration_
27
What is the most abundant AA in collagen?
Glycine (occupies every thrid AA position)
28
What molecules take on a trple helical conformation?
Collagen, due to repetitive AA sequences within each alpha chain
29
1. Most common cause of _homocystinuria_
2. What is the result of this defect?
3. How might this present clinically?
1. Homocystinuria is most commonly caused by a defect in _cystathionine sythase_
2. The result is an inability to form cysteine from homocysteine. Cysteine then becomes essential and buildup of homocysteine leads to elevated methionine
3. May present as _premature thromboembolic events_ (atherosclerosis, acute coronary syndrome, etc.), because homocysteine is **prothrombotic**
30
_Lesch-Nyhan syndrome_
Key presentation components (2)
1. Self-mutilation
2. Hyperuricemia
31
How can Isoniazid lead to sideroblastic anemia? Describe the process in detail (3 main steps)
1. Isoniazid (TB drug) inhibits pyridoxine phosphokinase, leading to a **vitamin B6 deficiency** (pyridoxine).
2. The active form of pyridoxine is a cofactor for **delta-aminolevulinate synthase**, an enzyme which catalyzes the rate-limiting step of _heme synthesis_.
3. Inhibition leads to **sideroblastic anemia**.
32
Which cell types, when metabolizing a single glucose molecule, will always ueild pyruvate but sometimes generate _NO_ net ATP?
(Explain this mechanism)
**Erythrocytes**
2, 3- BPG dec. hemoglobin affinity for O2. When 2,3-BPG needs to be synthesized, the RBC bypasses the step which converts 1,3 BPG to 3-phosphoglycerate, instead **forming 2,3 BPG in a process which does _not_ create ATP.**
33
_Primary Carnitine Deficiency_
1. What is the effect at the level of the cell?
2. Presentation
1. Deficiency in carnitine impairs fatty acid transport from the cytoplasm into mitochondria, **preventing B-oxidation of fatty acids into acetyl CoA**
2. Sx: _Cardiac_ and _skeletal myocyte_ injury (lack of ATP from Citric acid cycle) and impaired ketone body production by the liver during fasting periods
34
What is the role of NAD+ in glycolysis? How is NAD+ regenerated after reduction to NADH?
NAD+ is needed to convert G3P to 1,3-BPG
NADH then transfers electrons to pyruvate to form lactate and regenerate NAD+
35
What dz is associated with incorrect assembly of snRNPs? What is the specific mutation associated?
**Spinal Muscular Atrophy** (delayed motor development + flaccid paralysis)
SMN1 gene
36
_Pigment gallstones_
1. Composition
2. Appearence
3. Cause (including key enzyme)
4. What organism is often associated
1. Composed of Ca2+ salts of unconjugated bilirubin
2. Soft, dark brown or black
3. Typically arise secondary to **bacterial** or **helminthic infection** of the biliary tract. **_Beta-glucuronidase_**, released by injured hepatocytes and bacteria, hydrolyzes bilirubin glucorinides to unconjugated bilirubin
4. The liver fluke *Clonorchis sinensis* (high prevalence in East Asian countries), is a common cause
37
_Primase_
How is it related to uracil showing up in partially replicated DNA strands?
A DNA-dependent RNA polymerase that incorporates short _RNA primers into replicating DNA_
Because it is composed of RNA, this primer could have uracil in it
38
_Lesch-Nyhan Syndrome_
1. Inheritance
2. Specific defect
3. What are the results of this defect?
1. X-linked recessive
2. Defect in hypoxanthine-guanine phosphoribosyltransferase (**HGPRT**)
3. Results in failure of the purine salvage pathway leading to inc. _degradation of hypoxanthine and guanine to uric acid._ De novo purine synthesis must inc. to compensate via inc. **PRPP amidotransferase**
39
_Primary Myelofibrosis_
1. Presentation
2. Mutation
1. **Bone marrow fibrosis,** severe fatigue, _splenomegaly_ (often causing early satiety/abdominal discomfort), hepatomegaly, and anemia
2. Mutation: JAK2 (of the JAK-STAT signaling pathway-- tyrosine kinase)
40
What are the (3) options for Pyruvate metabolism and how do they occur?
1. **Lactic acid** (via lactate dehydrogenase in anaerobic conditions)
2. **Acetyl-CoA** (via pyruvate dehydrogenase in aerobic conditions)
3. **Oxaloacetate** (via pyruvate carboxylase)
41
What is the composition of fetal hemoglobin?
a2y2 (alpha 2, gamma 2)
42
Describe the key presentations associated with _thiamine deficiency_?
Beriberi and Werknicke-Korsakoff syndrome
1. **Wernicke-Korsakoff**- Confusion + occulomotor abnormalities + memory deficita + ataxia (**COMA**)
2. **Dry beriberi**- characterized by symmetrical peripheral neuropathy
3. **Wet beriberi**- includes the addition of high-output CHF
43
_Hormone Sensitive Lipase (HSL)_
1. Where is it found?
2. What is its function?
1. Found in adipose tissue
2. Functions to **drive the breakdown of stored triglycerides** into free fatty acids and glycerol. During times of starvation, this enzyme _provides substrates for hepatic gluconeogenesis and ketone body formation_
44
_Thiazide diuretics_
1. Indication
2. MOA
3. Effect on serum Ca2+
1. Primary HTN
2. _Inhibit the Na+/Cl- cotransporter in the distal tubule_, leading to inc. excretion of Na+ and H2O (as well as K+ and H+ ions)
3. **Increases distal tubular Ca2+ reabsorption**, causing both hypercalcemia and hypocalciruria
45
Name the (5) regions of the secondary structure of tRNA
1. **Acceptor stem** (mediates corrct tRNA recognition)
2. **3' CCA tail** (used as recognition sequence by proteins)
3. **D loop** (facilitates correct tRNA recognition)
4. **Anticodon loop** (used by the ribosome complex to select the right tRNA)
5. **T loop** (facilitates binding of tRNA to ribosomes)
46
What components are needed to do PCR? (4)
1. Primers that are complementary to the regions of DNA flanking the segment of interest
2. Thermostable DNA polymerase
3. Deoxynucleotide triphosphates
4. A source DNA template strand
47
_Tay-Sachs Dz_
1. Inheritance
2. Enzyme that is deficient
3. What accumulates?
4. Presentation
1. Autosomal recessive disorder
2. B-hexosaminidase A deficiency
3. GM2 ganglioside accumulation
4. _Presentation_: progressive neurodegeneration and cherry-red macular spot, **NO HEPATOSPLENOMEGALY**!!! (unlike Niemann-Pick dz)
48
49
1. What is the cofactor of phenylalanine hydroxylase?
2. What would be the presentation for a deficiency in either of these enzymes?
1. **Tetrahydrobiopterin**
2. Accumulation of phenylalanine in body fluids and the CNS. Homozygous infants are normal at birth but gradually develop **severe intellectual disabilities and seizures**. May also have **hypopigmentation** of skin, hair, eyes, and catecholaminergic brain nuclei
50
_Alkaptonuria_
1. Inheritance
2. Enzyme that is deficient
3. Presentation (3)
1. Autosomal-recessive disorder
2. Deficiency of **homogentisic acid dioxygenase** (an enzyme involved in tyrosine metabolism)
3. _Presentation_: (1) diffuse blue-black deposits in connective tissues, (2) adults have slerae and ear cartilage hyperpigmentation, (3) osteoarthropathy of spine and large joints
51
What is the role of transketolase and transaldolase? What cells can use them and for what purpose?
They carry out the **nonoxidative reactions of the HMP shunt** (Pentose Phosphate Pathway)
_All cells_ can synthesize ribose from fructose-6-phosphate using the nonoxidative rxns.
52
What does the smooth ER contain? What type of cells contain lots of smooth ER?
(In contrast to the RER,) the smooth ER contains **enzymes for steroid and phospholipid biosynthesis**. _ALL_ steroid-producing cells (adrenals, gonads, liver, etc.) contain a well-developed smooth ER.
53
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