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Foundations of Medicine > Week 3 Skildum > Flashcards

Week 3 Skildum Flashcards

TH4 and Cobalamin glycogen synthesis Purine/ pyrimidine metabolism Cholesterol metabolism

1
Q

What are the 3 ways single methyl groups are transferred in cells?

A

folate metabolism
vitamin B12 (cobalamin)
S-adenosyl methionine

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2
Q

What 5 substrates are used to donate into one-carbon pool?

A

Serine, Glycine, Histidine, choline, Formate

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3
Q

Which substrate is the most important source of since C groups for biosynthetic reactions?

A

Serine, single C is first bound to FH4 (tetrahydrofolate)

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4
Q

Where is folate found in the diet?

A

green leafy vegetables, liver, legumes, yeast, and fortified flour

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5
Q

What is digested by gut when folate enters the body that must be remade in liver?

A

poly glutamate tail

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6
Q

What is hereditary folate malabsorption?

A

inherited mutation in protein coupled folate transporter (PCFT)
-causes a functional folate deficiency despite adequate folate in diet

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7
Q

What causes spina bifida?

What is it?

A

folate deficiency before and during pregnancy

-defects in neural tube

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8
Q

What enzyme changes folate to dihydrofolate then to its active form tetrahydrofolate?

A 
dihydrofolate reductase (DHFR)
-uses 2 NADPH to activate to FH4
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9
Q

What drugs target DHFR?

A

methotrexate (cancer, rheumatoid arthritis), trimethoprim (antibacterial), pyrimethamine (antimalarial)

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10
Q

What does FH4 + formate create?

A

N10-formyl FH4 (can be used to make other oxidation states)

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11
Q

What is the Methyl trap?

A

Once 5-Methyl THF is made it can’t be reverted into other forms. ONLY can be used with cobalamin to make methylcobalamin

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12
Q

What does FH4 + histidine create?

A

FIGLU which releases NH4+ to make 5,10-Methenyl THF

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13
Q

What cofactor and enzyme are involved in serine to glycine reaction?

A

PLP is cofactor, enzyme is serine hydroxymethyl transferase

-methyl goes to FH4 to make N5-Nth-CH2-FH4 (5,10-methylenetetrahydrofolate) used with TS reaction to make dTTP)

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14
Q

What does FH4 + serine make?

A

N5N10-methylene FH4 (3rd possible product)

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15
Q

What 3 sources can make methylene-THF?

A

serine, glycine (reversible), and choline

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16
Q

What products can be made with methylene-THF?

A
  • serine
  • can regenerate glycine,
  • methyl-THF (then converted to methionine)
  • TMP + dihydrofolate –> DNA
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17
Q

What creates methenyl-TFH?

A

histidine + THF, to formimino-THF –> methenyl-TFH

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18
Q

What is formyl-THF used to make?

A

formyl-methionine
Purines
CO2

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19
Q

What are the 4 main products of one carbon donations?

A

thymidine nucleotide, purine bases, methionine, and S-adenosyl methionine

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20
Q

Which 3 forms of FH4 can be converted between?

A

10-Formyl THF, 5,10-Methenyl THF, and 5,10-Methylene TFH

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21
Q

What enzyme reduces a methylene FH4 carbon to methyl during its transfer to dTMP to make dTMP?

A 
Thymidylate synthase (TS)
-then must regenerate TH4 (reaction oxidizes it to TH2)
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22
Q

What type of anemia is caused by dietary folate deficiency? Why?

A

megaloblastic anemia, since dTMP can’t be made, DNA is not made. Few RBCs and ones left can’t divide

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23
Q

Where do the drugs 5-fluorouracil and methotrexate target?

A

5-flourouracil- stops thymidylate synthase (can’t form dTMP)

Methotrexate- targets dihydrofolate reductase

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24
Q

SAM does what?

A

Donates methyl groups to numerous substrates, including precursors to amino acids

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25
Q

Norepinephrine + SAM –>

A

Epinephrine

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26
Q

Guanidoacetate + SAM –>

A

Creatine

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27
Q

Nucleotides + SAM –>

A

Methylated nucleotides

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28
Q

Phosphatidylethanolamine + SAM –>

A

phosphatidylcholine

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29
Q

acetylserotonin + SAM –>

A

melatonin

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30
Q

What are the 2 types of cobalamin that can be formed?

A

methyl cobalain

adenosine cobalamin

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31
Q

In what reaction does N5-methyl TH4 donate its carbon?

A

to form methylcobalamin

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32
Q

What does methylcobalamin donate its C to? and what is the product

A

donates to homocysteine to make methionine

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33
Q

What does adenosylcobalamin donate its C to? and what is the product?

A

to methylmalonyl CoA to make succinyl CoA

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34
Q

What dietary sources can cobalamin (vitamin B12) be found?

A

meats, eggs, diary (either free or protein bound)

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35
Q

Where does the methyl group or adenosine bind cobalamin?

A

at the cobalt in the center of the ring

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36
Q

What binds cobalamin first in stomach and is then digested away?

A

R-Binder, secreted from gastric mucosa of stomach

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37
Q

What binds cobalamin after R-binder has been digested away?

A

intrinsic factor, produced in parietal cells

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38
Q

Where is cobalamin bound to intrinsic factor taken up?

A

by intestinal epithelial cells and transported in blood as a complex with transcobalamin 2 protein

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39
Q

What does B12 deficiency cause?

A

pernicious anemia (megaloblastic anemia plus neuropathy)

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40
Q

What can cause vitamin B12 deficiency?

A
  • dietary deficiency

- loss of function of intrinsic factor, transcobalamin 2, or cubillin

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41
Q

what is cubillin?

A

most intrinsic factor is stored in liver in complex with culillin

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42
Q

What enzyme converts methylmalonyl CoA to succinyl CoA using B12 Adenosyl cobalamin?

A

methylmalonyl CoA mutase (succinyl CoA enters TCA cycle to produce 1 GTP 1 NADH and 1 FADH2)

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43
Q

Which enzyme converts homocysteine to methionine using methylcobalamin?

A

methionine synthase, methylcobalamin must be remade after each reaction (by accepting methyl from N5-methyl TH4)

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44
Q

What is hyperhomocysteinemia?

A

result from mutations in methionine synthase, linked to cardiovascular and neurological problems (can’t convert it to methionine)

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45
Q

What are the 3 possibilities hyperhomocysteinemia can result from?

A

1) B12 (cobalamin) deficiency
2) methionine synthase deficiency
3) vitamin B6 (pyroxidal phosphate) deficiency

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46
Q

How is S-adenosylmethionine (SAM) formed? And what does it do?

A

methionine binds an adenosine nucleoside

-donates methyl groups to numerous substrates including precursors to neurotransmitters

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47
Q

Why does B12 deficiency result in functional folate deficiency?

A

irreversible formation of 5-Methyl THF (methyl trap) so it builds up and has no where to go without cobalamin to create methylcobalamin

48
Q

Why are neurological problems associated with B12 deficiency?

A

neurotransmitter precursors (epinephrine, creatine, methylated NTs, phosphatidyl choline, melatonin)

49
Q

What do defects in glycogen metabolism present as?

A

fasting hypoglycemia and muscle pain during exercise

50
Q

What are the 2 types of C-C bonds in glycogen?

A

1: 4 - linear chains
1: 6 - make branch points

51
Q

The addition of what molecule (and what enzyme) activate glucose 6P to make glycogen?

A

UTP, enzyme UDP glucose pyrophosphorylase. creates UDP-glucose

52
Q

What protein is the 1 C of UDP glucose attached to?

A

OH on glycogenin

53
Q

How long will chain grow until it will branch?

A

about 11 units long

54
Q

What enzyme catalyzes branching of glycogen?

A

glycosyl 4–>6 transferase

55
Q

What are the 2 key enzymes in glycogen synthesis?

A

glycogen synthase- adds on UDP glucose in 1:4 linkage

4:6 transferase- branching enzyme

56
Q

Why does glycogen form branched structure?

A

More active ends to cut off glucose and add onto

-increases solubility with more OH groups exposed

57
Q

What are the key enzymes in glycogen degradation?

A

glycogen phosphorylase- cleaves units of glucose 1 P from glycogen chain
-Debranching enzyme has 2 activities: 4:4 transferase (cleaves 1:4 glycosidic bond and transfers 3 glucose units to end of another chain) and alpha 1,6 glucosidase (hydrolyzes the remaining glucose’s 1:6 bond to release glucose

58
Q

Is glycogen phosphorylase A or B a more active enzyme? (Lineweaver- Burke plot)

A

A- more gradual slope so Km is smaller, and lower 1/Vm so Vmax is higher

59
Q

What are the states of glycogen phosphorylase B and glycogen synthase 1 (A) in fed state?
phosphorylated or not?

A

glycogen phophorlyase b = inactive
glycogen synthase 1 (a) = active
-neither phosphorylated

60
Q

What are the states of glycogen phosphorylase B and glycogen synthase 1 (A) in fasted state? phosphorylated or not?

A

glycogen phosphorylase b = active
glycogen synthase D (a) = inactive
-both are phosphorylated

61
Q

Is glycogen phosphorylase active or inactive when phosphorylated?

A

active.

62
Q

What is more prevalent in fed and fasted states? phosphatases or kinases

A 
Fed = phosphatases
Fasted = PKA and PKC kinase
63
Q

What is the main pathway for hepatocytes in fed state?

A

insulin binds, activates PDK –> PKB which phosphorylates protein phosphatase 1 (active)and glycogen synthase kinase 3 (inactive)
-active glycogen synthase, inactive glycogen phosphorylase kinase and no glycogenolysis

64
Q

What enzyme, only found in liver cells, allows glucose to leave?

A

glucose 6-phosphatase removes phosphate so unbound glucose can leave

65
Q

What is the extra indicator of fasted state in skeletal cells?

A

work generates AMP which activates AMP-K which also phosphorylates glycogen phosphorylase

66
Q

What is the process in skeletal muscle during fed state for glycogen metabolism?

A

insulin binds receptor –> PDK –> PKB which phosphorylates protein phosphatase (active) and glycogen synthase kinase 3 (inactive)

67
Q

What is GSD 0?

A

glycogen synthase deficiency

  • normal glucose tolerance, variable clinical presentation of exercise intolerance, cardiac and muscle hypertrophy
  • muscle specific
68
Q

What is GSD 1?

A

deficiency in glucose 6-phosphatase
-fasting hypoglycemia, lactic acidosis, hepatomegaly due to glycogen accumulation, hyperuricemia and hyperlipidemia (increased FA as starvation response)
Treatment: avoid fasting, frequent eating

69
Q

What is GSD 3?

A

deficiency of 1,6-glucosidase activity of debranching enzyme

-fasting hypoglycemia and ketoacidosis, hyperlipidemia, hepatomegaly with elevated AST/ ALT

70
Q

What are the 2 types of GSD 3 and what cells do they affect?

A

GSD 3a = affects liver and muscle

GSD 3b = affects only the liver

71
Q

What is GSV 4?

A

Deficiency of branching enzyme 4:6- transferase

  • failure to thrive, hepatomegaly, liver failure.
  • fatal (long chains of glycogen, not enough stores
72
Q

What is GSD 5?

A

deficiency of muscle glycogen phosphorylase

  • late childhood onset of exercise intolerance, myoglobinuria after exercising
  • starved cells break down themselves
  • lots of NH4+ after exercising
73
Q

How do bactericidal and bacteriostatic drugs differ?

A

bactericidal drugs reduce amount of bacteria (use if patient is immunocompromised) and bacteriostatic drugs limit growth to allow immune system to catch up

74
Q

What patient factors affect drug absorption, distribution, metabolism, and exretion?

A
  • absorption- movement of drug into vascular system
  • distribution- transfer of drug from intravascular to extravascular, blood brain barrier is challenge
  • Metabolism- irreversible transformation of parent compound into daughter metabolites, often in liver
  • excretion- elimination of the drug fro the body by urine or feces
75
Q

What is prophylactic therapy?

A

treat infection that has not developed yet in individuals at a high risk for becoming infected

76
Q

What is pre-emptive therapy?

A

have lab test indicating infection but no symptoms

-advantage = decreases amount antibiotics used

77
Q

What is empiric therapy?

A

take cultures, patients have an infection with serious potential consequences BUT organism has not been identified yet

78
Q

What is suppressive therapy?

A

after initial disease is controlled therapy, continued at a lower dose

79
Q

What is definitive therapy?

A

when pathogen is identified, monotherapy, narrow spectrum)

80
Q

What properties limit usefulness of a drug class and drugs within the class (toxicity)?

A
  • antibiotics need to injure invading organism wile causing minimal adverse affects to host
  • hard to make drugs for fungi, parasites, and eukaryotes since they are like us
81
Q

What mechanisms cause drug resistance?

A
  • intrinsic resistance (absence of target for drug, Mycoplamsa has no cell wall)
  • acquired drug resistance (change in bacterial DNA or acquire new DNA
  • DNA mediated transformation- acquire DNA from other bacterial cell
  • bacteriophage- can introduce DNA
  • Conjugation- exchange DNA, uses F pili, plasmid
82
Q

How can drug resistance be minimized or prevented?

A
  • take full round of antibiotics
  • don’t over prescribe
  • vaccinations to prevent infection
  • prevent transmission (isolate pathogen and break chain of contagion)
83
Q

What is the therapeutic index?

A

high therapeutic index means fewer adverse affects

84
Q

How can you determine alpha, beta, or gamma from hemolysis?

A

alpha hemolytic = green ring
beta hemolytic = clearing around colonies
gamma hemolytic = no hemolysis

85
Q

What is the nucleoside for adenine?

A

adenosine

86
Q

What is the nucleoside for the base guanine?

A

guanosine

87
Q

What is the nucleoside for the base hypoxanthine?

A

inosine (used as a fuel source)

88
Q

What is the nucleoside for the base cytosine?

A

cytidine

89
Q

What is the nucleoside for the base thymine?

A

thymidine

90
Q

What is the nucleoside for the base uracil?

A

uridine

91
Q

What is the first committed step in purine synthesis?

A

transfer of an amine from glutamine by glutamine phosphoribosyl amidotransferase
-creates 5 phosphoribosyl 1-amine

92
Q

How is PRPP formed?

A

-enzyme PRPP synthase converts Ribose 5-P from PPP to PRPP

93
Q

What allosterically inhibits PRPP synthase?

A

GDP and ADP (purine diphosphonucleosides)

94
Q

What does Glutamine + PRPP (plus a lot) finally make during purine synthesis?

A

IMP

95
Q

What 2 products can come from IMP?

A

+ glutamine to make GMP

+ aspartate to make AMP

96
Q

What enzyme converts XMP + Glutamine to GMP plus glutamate?

A

GMP synthase

97
Q

What protein redox cofactor takes OH to convert NDP to dNDP?

A

thioredoxin, 2 sulfurs can be oxidized (bridge) or reduced

98
Q

Which is the only nucleotide that can be directly phosphorylated to AMP by adenosine kinase?

A

adenosine

99
Q

Which enzyme deficiency is associated with Lesch-Nyhan Syndrome?

A

HGPRT (hypoxanthine- guanine phosphoribosyltransferase)

  • X linked disorder
  • self injury, elevated uric acid, often die in 30s from renal failure
100
Q

What does a deficiency in purine nucleoside phosphorylase (PNP) cause?

A
  • can’t convert inosine to hypoxanthine or guanosine to guanine
  • low T cells, chronic infections, buildup of insoine is toxic to developing T cells and lymphocytes
101
Q

What does a deficiency in adenosine deaminase (ADA) cause?

A
  • autosomal recessive SCID (severe combined immunodeficiency)
  • accumulation of 2-deoxyadenosine in blood
  • low lymphocytes and costochondral junction dysplasia (skeletal abnormalities)
  • treatment is bone marrow transplant
102
Q

What is gout caused by?

A

hyperuricemia (too much uric acid in blood)

  • from purine degradation, xanthine oxidase isn’t working
  • salt crystals can form in fingers and toes
103
Q

What do GMP and AMP degrade to? and by what enzyme?

A

xanthine

-xanthine oxidase

104
Q

What enzyme starts path to convert glutamine (as N donor) to UMP in pyrimidine synthesis?

A

CPS 2 (carbamoyl phosphate 2) in cytoplasm

105
Q

What are the 2 products of pyrimidine degradation? Are they harmful?

A
  • beta alanine
  • beta aminoisobutyrate
  • no pathologies from accumulation
106
Q

What are the main features of cholesterol?

A
  • 4 rings
  • fully saturated
  • branches
107
Q

What is the key regulatory enzyme in cholesterol synthesis?

A

HMG CoA reductase

-HMG-CoA to Mevalonate

108
Q

What type of drug inhibig HMG CoA reductase?

A

statins

109
Q

How many HMG CoA reductase enzymes are there? Where are they found?

A
  1. 1 in mitochondria for ketone body synthesis and 1 in cytosol for cholesterol synthesis
110
Q

What Apo protein do al chylomicrons have?

A

Apo B-48

111
Q

What Apo proteins do mature chylomicrons have?

A

Apo B-48, Apo C-2, Apo E

112
Q

What are chylomicrons composed of?

A

mostly TAGs, some proteins, cholesterol, cholesterol esters, and phopholipids

113
Q

What causes congenital adrenal hyperplasia and what are the symptoms?

A
  • mutation in steroid hormone biosynthesis gene Cyp21
  • low aldosterone and cortisol
  • high androgen levels
114
Q

What are xanthomas?

A

Cholesterol rich tumors on body, from familial hypercholesterolemia/ too much LDL in blood

115
Q

What is vitamin D important for in body?

A

Calcium homeostasis

Foundations of Medicine (7 decks)

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