Block 3 Flashcards
1
Q
What’s the first vitamin that we have a shortage of during fat malabsorption?
A
We dont’ store Vitamin K very well so its’ the first vitamin that we have a shortage of during fat malabsorption
2
Q
What kind of bond holds PLP as a side group? What residue is it attached to? What reactions is PLP required in?
A
Lysine - schiff base;
PLP used in:
transamination;
Heme synth (ALA synth in HEME pathway);
Dopamine synth (from Tyrosine/Dopa);
GABA formation (from glutamate);
Threonine --> Glycine
Tryptophan --> Serotonin (second step)
Glycogen phosphorylase
3
Q
What calorie source has the highest Respiratory question/DIT?
A
Carb 1.0 fats 0.7 protein 0.8 RQ
DIT: Protein is highest
4
Q
What 4 amino acids indicate that the proteins have short half lives? What AA is the most common indicator of short half life?
A
PEST - Proline Glutamate Serine Threonine;
aspartate on N terminal position is most imp’t 3 minutes h/l
5
Q
What do transaminases require to remove an NH2? Describe transaminase specificity; what does presence of transaminase in blood signal?
A
PLP (Vit B6 Pyridoxal Phosphate) attached via schiff base transaminase is specific alpha-keto-acid is not; transaminase in blood signals liver damage
6
Q
Which isoform of amino acids can we use? What are the 9 essential amino acids? Which are purely ketogenic?
A
L isoform (D are for dog), pvt tim hall, lysine and leucine
7
Q
Which amino acids are directly convertible to TCA intermediates?
A
Aspartate –> OAA
Alanine –> Pyruvate
Glutamate –> A-KG
8
Q
What nicotinic acid molecules are involved in the amination or deamination of glutamate? Glutamate is the only amino acid that can do what? What enyzme is involved?
A
NAD-> NADH for deamination NADPH–> NADP; accept free NH3; glutamate dehydrodgenase
9
Q
What types of AA’s don’t require sodium for their cotransport in the GI tract?
A
Aromatic (try trp phe) and BCAA (valine leu isoleucine)
10
Q
Build up of BCAA’s is caused by and results in? WHere does this breakdown normally happen? What are the BCAA’s anyhow?
A
Defic. in BC k-acid DH (a TLCFN enzyme) results in Maple Syrup Urine disease (MR acidosis sweet smelling urine); Tx: Thiamine (TLCFN) restrict BCAA’s; skeletal muscle; I LV - Isoleucine Leucine Valine
11
Q
Two methods for protein breakdown? What does each require?
A
Proteasome with ubiquitin tag on NH2 of Lysine or by Calpain binding to the protein (then autolysis small portion becomes active and proteolytic) requires Calicum
12
Q
Regulatory enzyme for urea cycle and its substrates? What is it’s activator (and what’s the activator’s activator?)? Most commonly deficient enyzme in pathway and it’s reprecussions? What other condition can that be compared to and what are the differentials? Final enzyme and products in pathway?
A
Carbomyl Phosphate Synthetase I (Mito) 2 ATP CO2 (bicarb) and NH3/4 (from glutamine/glutamate); NAG; N-acetyl glutamate which itself is activated by arginine; Ornithine Transcarbamoylase failure leads to hyperammonemia and orotic acid build up; differentiate from orotic acid buildup from uridine monophosphate synthetase (from pyrimidine cycle) by hyperammonemia and lack of megoblastic anemia; Final enzyme is arginase producing ornithine and urea
13
Q
urea cycle failure consequences and affected organs?
A
Causes hyperammonemia and encapalopthy; a-k-g stolen from TCA leads to energy deficicency; If liver failure you get hepatic encephalopathy (due to aromatic acid building up and damaging nervous tissue; HIGH BUN –> renal damage (kidney not excreting urea); low/normal BUN –> liver damage
14
Q
PKU: When do you test for it and why?
A
Minimum 12 hours after birth becuase prior to that PAH (phenylalanine hydroxylase) is not produced;
15
Q
Amino acids that can be converted to glutamate:
A
Histidine glutamine; proline; arginine;
16
Q
What is our primary 1-C carrier? What are it’s two main sources of Carbon?
A
Tetra-hydroflate and Glycine/Serine
17
Q
Three things that serine can be converted to (enzyme and cofactor)?
A
Glycine (serine hydroxy methyl-transfersase FH4) Cysteine (cystathione transferase PLP) Pyruvate (Serine dehydratase (no cofactor gives off free NH4)
18
Q
Formation of FH4/TH4 from Folic Acid requires what enzyme and cofactors?
A
Dehydrofolate reductase and 2 NADPH
19
Q
How does hyperglycinemia present and what is it’s cause? how about histidinemia? Homocystinuria?
A
hyperglycinemia: severe MR non-stop hiccuping; overabundance of glycine is bad (major inhibitory neurotransmitter due to failure of glycine cleavage enzyme);
histidinemia: usually histidase defic (mental retardation catabolic histidine products in CNS); also may be due to defic in TH4 or Formino Transferase (figlu accumulation in urine)
Homocysteinuria: accum. of homocysteine; methionine; dx: funnel chest resembles marfan CVD (atherosclerosis); Tx: restrict methionine Vit B6
20
Q
Reactions that require FH4:
A
Histidine –> Glutamate;
Serine –> Glycine;
glycine cleavage –> CO2/NH3;
homocysteine –> methionine (by way of B12/cobalamin);
21
Q
What bile conjugate is formed from cysteine? What is cystinosis (mechanism and effects)?
A
Taurine; Defective lysosomal transporter; leads to photophobia tearing blindiness polyuria glucosuria
22
Q
Why is Lysine one of the last AA’s that is ever broken down? What cofactor does it’s product require for formation?
A
Because Lysine is used to make Carnitine (necessary for FA oxidation) requires 3 SAM’s == 9 ATP
23
Q
What enzyme is at the root of malignant PKU and what is it’s cofactor? Regular PKU?
A
Dihydropteridine reductase (recycles BH4 using NADPH); Regular PKU is due to defic. in PAH whcih uses BH4 to hydroxylate Phe –> Tyrosine
24
Q
What are PAPS for and what is their source?
A
Attach SO4 to sugars (like GAGs) or to make drugs more soluble; made from Cysteine
25
What reactions is B12 required in? Deficiency results in?
As methyl cobalamin converts homocysteine to methionine also recycles met-FH4 to FH4; without it you get folate trap (all FH4 tied up) pernicious anemia
26
Source of glyoxylate? What does accumulation lead to?
Glycine oxidation; leads to oxalate buildup/kidney stones
27
What 5 things can you mke from Tyrosine (and where did you get tyrosine from anyhow)?
Tyrosine comes from phenylalanine; products include: melanin; thyroid hormone; dopamine; norepi; epi
28
Failure of degradation of Tyrosine leads to 2 conditions; what are they what’s the enzyme involved (cofactor if any) and what are final products of tyrosine breakdown?
Homgentisate oxidate deficiency requires Ascorbate as a cofactor results in alkaptonuria (black urine buildup in joints of elderly; Fumyrlaacetoacetate hydrolase --> tyrosinemia I (cabbage like odor impairment of renal tubular abosrb; liver failure);
Final products: fumarate and acetoacetate
29
Degradation of Trhyptophan requires what enzyme and cofactor? What essential product does it form? what other two handy things do you get from this breakdown?
Cleavage of pyrolle ring by pyrrolase requires NADPH used to form Niacin/Nicotinc acid (for NADH NADPH); also released ketone and alanine
30
What are the two initial components of heme? What’s the regulatory enzyme and what down-regulates this enzyme and what cofactors does it have? Any other way heme synth is regulated?
Heme: initial step is regulatory EXCEPT in the bone marrow!!; ALA synthase; requires PLP as cofactor combines Succinyl CoA and Glycine; down-regulated by heme or heme-like hematin (Fe3+); Bone marrow only by Fe availability
31
How can lead interfere with Heme and what metals is it replacing?
Can substitute for Zn in ALA dehydratase or for Fe++ in ferrochelatase
32
Most common porphyria? Only one that is AR? Which important one is not photosensitive?
Porphyria Cutanea Tarda (photosensitivity; red-brown urine; uroporphobillinogen decarboxylase creating croproporphyrinogen; CEP (congenital erythropoetic porph; photosens; scarring infections loss of digtis);
Acuite Intermittent Porphyria; no photosensitivity due to porphobillinogen deaminase (that takes 4 porphobillinogen and makes them into a ring hydroxymethylbilane)
33
What specifically breaks down heme using what initial enyzme? What is the intermeidate product and what is it converted to? What’s special about the iron that comes out of Heme and what do you have to do about that specialness?
Macrophages in the spleen; enyzme is heme oxygenase (a P450 that contains Heme) which generates biliverden; biliverden reductase converts that to billirubin which is carried by albumin to the liver; Iron from heme breakdown is Ferric (Fe3+) so has to be reconditioned to Fe2+ by Vitamin C
34
What does the liver do with bilirubin and with what enzyme? When this product is secreted what three things does it become during breakdown?
In liver billirubin is conjugated with 2 glucuronates by bilirubin glucuronyl-transferase; conjugated bilirubin is secreted as bile and broken down by bacteria to urobillinogen; further broken down to urobillin (excretion in urine) or stercobillin (excretion in feces)
35
Describe the three kinds of jaundice (hemolytic neonatal and nuclear) as well as dubin-johnson syndrome
Hemolytic jaundice: massive break down of RBC’s (malaria sickle cell) overwhelms liver;
Neonatal jaundice: neonate has lg. amount of Hb that needs to be broken down along with naturally low glucuronyl transferase activity;
nuclear jaundice: bilirubin accumulating in lipid rich area of brain - CNS issues ensue
Dubin-Johnson: failure to secrete bilirubin into bile leads to black liver hyperbilirubinemia
36
Products of Arginine? Which involves vasodilation and clotting and in what way for each? what popular drug takes advantage of this process?
urea Nictric oxide and creatine; Nitric oxide is released (and produced) by endothelium prevents platelet aggregation (also immunogenic) relaxes vessels through guanylate cyclase production of cGMP (much like cAMP release in smooth muscle); viagra
37
Creatine synthesis involves what two AA’s? What does creatine randomly break down into?
Creatine is formed from combination of arginine and glycine (releasing ornithine); creatine phosphate spontaneously cyclises to creatinine and is excreted in urine
38
Which amino acids or products are neurotransmitter?
```
Glutamate --> GABA
Serine --> Glycine (inhibitory)
Arginine --> NO
Tyrosine to Dopamine Norepi Epi
Tryptophan --> serotonin
```
39
Two ways to get rid of histmaine?
Diamine oxidase in peripheral tissue (releases free NH4)
| SAM and MAO-B in brain (MAO also breaks down catecholamines)
40
What produces Serotonin and what cofactors are involved? What is Seratonin later converted to (and using what two cofactors) ?
Tryptophan using tryptophan hydroxylase (with BH4) then dopamine decarboxylase (PLP);
Serotonin gives rise to melatonin using AcetylCoA and SAM
41
Two ways to get rid of histmaine?
Diamine oxidase in peripheral tissue (releases free NH4)
| SAM and MAO-B in brain (MAO also breaks down catecholamines)
42
What produces Serotonin and what cofactors are involved? What is Seratonin later converted to (and using what two cofactors) ?
Tryptophan using tryptophan hydroxylase (with BH4) then dopamine decarboxylase (PLP);
Serotonin gives rise to melatonin using AcetylCoA and SAM
43
What are Tyrosine’s catecholamine products and what cofactors does it use? What degrades the catecholamines? What happens if the cells producing the second product are destroyed?
Tyrosine --> Tyrosine hydroxylase --> Dopa (using BH4 and Cu2+)
Dopa --> Dopamine use dopadecarboxylase (and PLP)
Dopamine --> Norepi use Cu++ and Vitamin C
Norepi --> Epi using SAM;
Catecholamines degraded with MAO and COMT (catechol-o-methyltransferase);
If cells producing dopamine are destroyed result is Parkinson’s disease
44
Aside from catecholamines what are two products does Tyrosine create and what are co-factors for each?
Thyroid hormone using H2O2 (and idoine) Melanin - via Tyrosinase requiring Cu and UVB light (pheomelanin pink eumelanin dark)
45
What do purines need to start from that pyrimidines don’t and where does it come from? What three AA’s do you need? What inhibits both regulatory steps?
PRPP scaffold created by PRPP synthetase (activated by Pi inactivated by AMP/GMP/IMP (products); needs Ribose-5-phosphate from HMP shunt and two phosphate from ATP;
Three AA’s for purines: Aspartate Glutamine Glycine
nucleotides inhibit both steps
46
What takes you from IMP to either AMP or GMP? What about to GTP/ATP?
IMP --> AMP requires GTP and aspartate (this process slowed by AMP)
IMP --> GMP requires ATP and glutamine (this process slowed by GMP)
Upgrade of GMP or AMP requires ATP with either adenylate kinase or guanylate kinase and then NDP kinase
47
What enzyme allows you to salvage Adenine? Guanine? Hypoxanthine?
APRT HGPRT HGRPT
48
What two conversions can Xanthine oxidase make? What is xanthine oxidase’s cofactor?
Hypoxanthine --> xanthine and then xanthine -> uric acid and H2O2 with molybdenum as a cofactor
49
Excessive xanthine oxidase activity can produce large amonts of what? What the’s difference between Lesch Nyhan and Tophaceous gout? What’s the treatment for gout and what does it do? What’s an early sign of Lesch nyhan?
Uric acid; Gout is the buildup of uric acid crystals in joints; treated with allopurinol (which inhibits Xanthine oxidase); Lesch Nyhan is result of HGPRT mutation accumulation of hypoxanthine and guanine; MR chewing off lips fingers and tongue; uric cyrstals in urine; early sign is pink/orange wet diaper
50
What does Mycophenolic acid do? What cells of the body are affected and why would you do this?
Uncompetitive inhibitor of IMP dehydrogenase deprives T cells and B cells of nucleic acids prevents graft reduction
51
What aspect of purine salvage can lead to SCID? What drug does this resemble to you?
Adenosine Deaminase deficinecy can lead to scid; deoxyAdenosine sugars pile up interferes with production of nucleic acids for T cells and B cells severely immunocompromised
Just like mycophenolic acid for graft rejection prevention
52
What’s teh regulatory enzyme of pyrmidine synth and what regulates it? What are its substrates?
Carbomoyl phosphate Synthetase II (in cytosol!)
Requires 2 ATP and glutamine and CO2 (glutamate for the NH3)
Regulated by: GRPP (activates it) UTP (inhibits it)
53
How can pyrimidine synthesis lead to orotic aciduria? What are the symptoms of this?
Orotate is made when carbamoyl phosphate is combined with aspartate;
blocks in UDP synthase (which has a transferase domain and a decarboxylase domain) lead to build up of orotic acid in teh blood;
symptoms include poor growth megoblastic anemia high orotate in urine NO HYPERAMMONEMIA acidifies blood
54
what substrates do you need to make CTP? dTMP? How and why is dTMP synthesis blocked (2 ways)?
You need UTP and Glutamine to make CTP;
dUMP is require do make dTMP;
dTMP can be blocked at thimydlylase synthase (which requires FH4) with 5-flurouracil (fights breast cancer)
of
at DHF reductase whcih using NAPDH recycles the FH4 that Thimydylate synthase uses to create dTMP. This is blocked with Methotrexate also an anti-cancer drug
55
How is UV light related to pyrimidines?
UV can cause dimers as well as OH and O2 radicals
Defective UV specific endonuclease can cause mutations and cancer if these aren’t cut out properly.
Methylated cytosines can also become thymines leading to under rep of methylated cytosines in humans.
56
What does ribonucleotide reductase do and what does it need to do it? What is the source of 2 components of this rxn?
Ribonucleotide reductase removes OH from ribose to make it deoxy-ribose; requires Thioredoxin (2 sulfur group) and NADPH; both NADPH and ribose from HMP shunt
57
Describe the 3 types of UV light and their effects
UVA - damages collagen and vitamin A
UVB -causes sunburn and skin cancer pyrimidine dimerization double bonds absorb light - used in Vitamin D synthesis
UVC- most toxic but is absorbed used as germicide
58
Most important trace metal transporter? What metals does it transport?
Transferrin for Iron Zinc and copper
59
How is most copper stored? What is the result of over abundance of copper? What is result of insufficiency? Which state does hyperglycemia cause?
Most Copper (60%) is bound to ceruloplasmin
Deficiency of Copper leads to Menke’s
brittle hair MR seizures microcytic anemia
Cause: Deficient ATP dependent Cu transporter
Toxicity: Wilson’s Disease
Biliary Cu excretion is blocked
Hyperglycemia causes ceruloplasmin to rise causing Wilson’s disease
60
Name 3 enzymes that use Zinc; what does deficiency cause (symptoms and a specific disease)
Zinc deficiency causes poor growth testicular atrophy delayed sexual dev’t dermatitis
Also leads to Acrodermatits Enteropathica
dermatitis hair loss diarrhea
61
Deficiency in Selenium leads to what (including symptoms)? Who tends to not have much?
Defic. in selenium leads to Keshan disease (cardiomegaly impaired ROS defense); criminals have very low selenium in diet
62
How is Fe3+ reconditioned? What type of Fe can we absorb? What protein stores Iron? What disease follows from inability to reduce Fe3+?
Vitamin C (ferric reductase) converts Fe3+ --> Fe2+; most that isn’t in RBC’s is bound to Ferritin; Refsums disease: phytic acid blocks Fe3+ reduction activity leading to microcytic and hemolytic anemia
63
What two conditions arise from iron toxicity? What does hemosiderin do?
Hemosiderosis (free radical formation)
Hemosiderin normally picks up Fe3+ when Fe stores are high
Hemochromatosis - Organ damage hyper pigmentation
often found in alcholics because alcohol stimulates absorption
64
Where is Thiamine used as a cofactor? What two diseases arise from deficiency?
Thiamine as TPP - co factor for:
Transketolase
TLCFN dehydrogenases (PDH BCAA DH A-K-G DH)
Diseases from defic:
Beriberi - caridovascular and neuromuscular issues;
letharghy weakness
Wernicke-Korsakoff syndrome:
Memory loss and mental derangment common in alcoholics
65
Where do you see Pantothenic acid used primarily? What about biotin? how is it connected as a prosthetic group
Pantohenic acid (B5) - Fatty acid synthase component
Biotin - Vit H - ABC carboxylases (AcetylCoA carboxylase pyruvate carboxylase for gluconeogenesis propionylCoA carboxylase MethylMalonyl Carboxylase)
Connected via Schiff base through Lysine
66
Three big roles that we care about vitamin C for? Shortage leads to:
Vitamin C: does reduction (like of Fe3+) hydroxylation rxns with lysine and proline in collagen formation; dopamine --> Norepi
Shortage --> scurvy
67
What’s Vitamin B3? What does shortage lead to? Where else can we get it from?
B3 == Niacin Nicotinic acid - precursor to NAD/NADP
Shortage leads to weakness anorexia indigestion permanent mental changes
Can also get Niacine from Tryptophan breakdown
68
What is the only water soluble vitamin that can be toxic at high levels? Whoe does it happen to?
Pyridoxal phosphate (B6) - toxic at high levels happens to alcoholics
69
What two key coenzymes do we get from Vitamin B9? What AA does it contain? What can deficiency of B9 cause?
B-9 (Folate) gets us:
BH4 (reducing agent)
FH4 (tetrahydrofolate) - 1-C carrier
B-9 contains Glutamate
Deficiency can lead to megaloblastic anemia in pregnant women and neural tube defects
70
What two rxns does B12 participate in? What do we need to absorb it? What does shortage cause?
B12
MethylMalonyl-CoA Mutase coenzyme (breaking down Propionyl CoA)
Transfers methyl group in methionine synth from homocysteine
Absorbed using IF
Deficiency leads to megaloblastic anemia pernicious anemia
71
What is B2 used for? Deficiency leads to?
B2 is riboflavin and is used for FAD and FMN
| Deficiency: glossitis sore throat moist dermatitis of nose
72
What are the two main active forms of Vitamin A and what are they used for? what does deficiency in either lead to? What is it’s precursor? How is it stored/carried?
Retinal (part of rhodopsin - light sensing); deficiency leads to night blindness
Retinoic acid: gene transcirption for maintenance of epithelia and membranes;
deficiency: columnar epithelia become keratinized loss of mucus secreting cells from the eye (xerophthalmia) -> leading cuase of blindness
precursor is beta kerotene
carried by Retinol binding protein stored in stellate cells
73
Why do pregnant women need to avoid accutane?
Vitamin A is used to treat acne but it’s hugely teratogenic
74
What do you need to make vitamin D? Why are infants sometimes deficient? What’s the active form called and where is it made (three places)? What disease does defic. in active form lead to?
UVB; calcitriol; starts in skin then liver to calcidiol then kidney activated to calcitriol; Deficiency leads to calcium being resorbed from bone so either rickets or osteoperosis
75
What vitamin (aside from K) has a role in blood clotting? What mineral? What is vitamin K’s role in blood clotting? Why are infants deficient and what does it lead to?
Vitamin E also has a role in clotting by INHIBITING platelet aggregation
Calcium is a cofactor of coagulation 10a 9a
Vitamin K’s clotting role: post-translational carboxylation of Gla (glutamate) residues of clotting factors:
10 9 7 2 C (XIV) S
Breastfeeding infants may not get enough from mother’s milk leading to hermorrhagic disease of the newborn
76
What enzyme cleaves trypsinogen? What then cleaeves the rest of the peptidases?
Enteropeptidase cleaes trypsinoen and then trypsin cleaves everything else (trypsin chymotrypsin elastase carboxypeptidase
77
What is adiponectin? Who secretes it? What effect does it have on AMPK and what does that do anyhow?
Adiponectin comes from adipocytes; elevates beta oxidation and inhibits lipogenesis and gluconeogenesis.
Activates AMPK which increases FA uptake beta oxidation and glucose uptake
AMPK decreases synthetic rxns like FA synth
78
What is ghrelin? Is it orexigeninc or anorexigenic? What about leptin?
Grehlin is from the stomach release of orixogenic hormones (this is good let’s eat more) - therefore orexogenic
Leptin - secreted from adipose tissues - appetite suppressor (anorexogenic)
79
How does the body maintain glucose levels during prolonged (like 40 days) fasting? What is the source of this gluocse?? What organ(s) produce this glucose?
First few hours of fasting: glycogen from liver (up to 18 hours)
after 18 hours or so gluconeogenesis dominates;
glucose produced primarily from amino acids (alanine) but also from glycerol
Gluconeogenesis is taking place in the liver and the kidney
80
What does the body use aside from glucose? Which tissues never switch to alternate fuel sources?
After ~6 days the body switches to fatty acid and ketone usage
RBC’s and Renal medulla NEVER switch to ketones
81
What are the two types of semi-starvation and what differentiates them?
Kwashiorkor - rel. normal caloric intake but diminished protein intake
Decreased serum albumin leads to edema
Prone to decompensation - secondary infections as body is unable to defend itself
Marasmus:
inadequate calories of all types
STRONG resistance to infection
still has anti-microbial peptides/host defennse peptides
82
What’s the difference between the two types of Diabetes? What mutation is involved in one of them?
Type 1 - some loss of pancreatic beta cells so body can’t produce insulin
requires exogenous insulin for life
mutations related to IDDM on chrom 6 in HLA region
83
What can clot serum or plasma? What’s it called when clots are broken down?
Plasma can clot serum cannot.
| Fibrinolysis is the breakdown of clots
84
What are the four big events of blood clotting?
1. Vasodilation
2. Platelet actviation which is made up of:
a. adhesion
b. aggregation
c. secretion
3. Formation of fibrin meshwork
4. Clot dissolution (fibrinolysis)
85
What’s the main effector protease of the coagulation cascade? What’s the most important adhesion reaction in clotting?
Thrombin is the main effector protease of coagulation!!
| Most important adhesion reaction is GB1b to collagen VIA the Von willebrand factor
86
What’s in dense granules of platelets? Alpha granules?
Dense granules: ADP Serotonin (vasoconstriction) and calcium
Alpha granules: VWF and fibrinogen
87
During aggregation what’s holding platelets together? What induces aggregation? What drug interferes with this?
Fibrinogen is the bridge between activated platelets! They connect via GPIIb/GPIIIa dimers
Plavix blocks this interaction
88
What key enzyme produces thromboxanes? What does thromboxane do? What inhibits this enzyme?
Thromboxanes are potent platelet activators
COX - Cyclo oxygenase - produces these
Inhibited by NSAIDS so less thromboxane around to activate platelets
89
What are the 4 agonists of platelet aggregation? What kind of receptor do they work on?
All work on G coupled receptors:
| ADP Thrombin Thromboxane Collagen
90
What are von Willebrand’s factors TWO big jobs?
1. Adhesion of platelet to injured vessel wall (GP1b --> collagen)
2. Stabilizes clotting factor 8
91
Types of VWF disease:
Type 1 vWF: 80% of cases bascially lower quality protein bad folding etc.
Type 2: Missense mutations affect processing lots of dimers mutation in the region responsible for proteolytic cleavage
Type 2b: gain of function:
abnormal affinity for platelets leads to clumping of platelets in in circulation
Type 3:
severe vWF deficiency also deficient in factor 8
includes deletion of the gene
92
Most clotting factors are zymogens; what activates them? What does this activator need?
All blood clotting zymogens are cleaved by serine proteases
| Serine proteases have to bind to their cofactor on the membrane
93
What are the most important cofactors of the clotting cascade? Who activates most of the co-factors?
8a co factor for 9 (which converts 10 --> 10a)
5a ---> cofactor for Factor 10 (cleaving pro-thrombin to thrombin)
5 and 8 are both activated by Thrombin
94
What are the two most important proteins of the extrinsic pathway? What happens after they bind?
Tissue factor and Factor 7 combine to become TF:VIIa which then activates factor 9 --> 9a (who then activates 10
95
What enables clotting factors to bind to the negative plasma membrane?
GLA domains - carboxylated glutamate residues
| This happens during biosynthesis and is done by Vitamin K
96
What activates thrombomodulin? What is it’s role?
Thrombomodulin is activated by thrombin when it’s at high concentration.
Thrombomodulin activates protien C which joins with protein S to destroy Factor 5a and factor 8a
97
What’s factor 5 leiden?
Factor 5 leiden is a common point mutation in factor 5 gene that makes it resistant to degradation by activated protein C
98
What’s wrong in hemophilia?
Factor 8 (for A) or factor 9 (for b) are faulty(long arm flipping on X chromosome)
99
What does factor 13 do?
Factor 13 is a transgluamidase
| Cross links the soft clot with covalent bonds between lysine and glutamine
100
So thrombin stops clotting what breaks up the existing clot? What activates this monster?
The serine protease PLASMIN
Constantly circulating as plasminogen converted to plasmin by two serine proteases:
tPA (tissue type plasminogen activator)
uPA (urinary type plasminogena ctivaotry)
101
What are some common anti-coag drugs and how do they work?
Coumarin drugs like warfarin- antagonizes vitamin K so that carboxylation of the clotting factors (10 9 7 2 C S) doesn’t happen (all of these have that GLA domain)
Pradaxa - inhibits factor 10a or thrombin itself
Plavix - blocks GPIIb/IIIa interaction with fibrinogen too much mimics glanzmans
102
What is metalothionein?
body's main store of Zinc protects cell from toxic effects of free unbound heavy metals
103
Deficiency in what two enzymes can lead to scid?
Adenosine deaminase
or
Ribonucleotide reductase
104
Deficiency in porphobillinogen deaminase causes?
| What about uroporphyrinogen III cosynthase
AIP
| CEP
105
five amino acids are both ketogenic and glucogenic:
```
IPTTT
Isoleucine
Pheynalanine
Tryptophan
Threonine
Tyrosine
```
