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Metabolic Pathways > Lecture 1 (1A) - Folate and Vitamin B12 > Flashcards

Lecture 1 (1A) - Folate and Vitamin B12 Flashcards

1
Q

Coenzymes and cofactors

A
  • additions to protein function
  • essential for function of enzyme
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2
Q

Coenzyme

A

a small molecule essential for the activity of some enzymes

  • not protein, usually vitamins
  • a cofactor molecule that helps an enzyme catalyze a particular reaction by binding with it
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3
Q

Cofactors especially in

A

electophilic catalysis

  • catalysis by a Lewis acid (any chemical species that abstracts an electron pair from the reactant)
  • cofactors altered in reaction = need regeneration
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4
Q

Coenzyme examples

A
  • biotin –> carboxylation (carrying carbon around)
  • flavin coenzymes –> oxidation/reduction (membrane-bound processes)
  • nicotinamide coenzymes –> oxidation/reduction
  • pyridoxial phosphate –> amino group transfer
  • cobalamin (B12) coenzymes –> alkylation
  • tetrahydrafolate –> C1 (one-carbon) unit transfer (active form of folic acid
  • we can’t synthesize it but in green veg and synthesized in bacteria)
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5
Q

Folic acid

A
  • abundant in green vegetables
  • synthesized by bacteria
  • from diet in animals (we can’t synthesize it)
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6
Q

Folic acid structure

A

2-amino-4-oxo-6-methylpterin + ρ-aminobenzoic acid (ρ-ABA) + glutamates

• pteridine ring is very important

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7
Q

The active form of folic acid

A

tetrahydrofolate (THF)

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8
Q

THF carries C1 on

A

N5 or on N10 or both

• transfers C1 units in different oxidation states

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9
Q

3 oxidation states of THF

A
  • methanol
  • formaldehyde
  • formate
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10
Q

Increasing states of oxidation

A
  • methyl
  • methylene
  • formyl, formimino, methenyl
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11
Q

Differing THF derivatives

A
  • N5 - Methyl - THF
  • N5,N10 - Methylene - THF
  • N5 - Formyl - THF
  • N10 - Formyl - THF
  • N5 - Formimino - THF
  • N5,N10 - Methenyl - THF
  • THF derivatives interchange
  • in equilibrium
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12
Q

C1 entry into C1 unit pool

A
  • 4 routes
  • main entry routes = serine, glycine
  • less so = histididne • even less = formate
  • all use THF for entry
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13
Q

THF derivatives interchange, ATP…

A

if ATP is generally needed for a reaction, it will most likely be one way with no back reaction because so much energy was required to drive it in the first place

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14
Q

Entry reactions

• enzyme = serine hydroxymethyl transferase

A

serine + THF

==>

glycine + N5,N10-Methylene-THF

• transferring hydroxymethyl from serine to another molecule

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15
Q

Entry reactions

• enzyme = glycine synthase (working in reverse)

A

glycine + NAD+ + THF

==>

CO2 + NH4+ + NADH + N5,N10-Methylene-THF

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16
Q

Entry reactions

• enzyme = glutamate formimino transferase

A

histidine + THF

==>

glutamate + NH4+ + N5-formimino-THF

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17
Q

Entry reactions

• enzyme = N10-formyl-THF synthetase

A

formate + ATP + THF

==>

ADP + Pi + N10-formyl-THF

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18
Q

Enzymes ending in -etase

A

usually associated with an APT event

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19
Q

Coenzyme: biotin

A

carboxylation

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20
Q

Conezyme: flavins

A

oxidation/reduction

(membrane bound processes)

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21
Q

Conenzyme: nicotinamides

A

oxidation/reduction

(soluble proteins - flavins)

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22
Q

Coenzyme: pyridoxal phosphate

A

amino group transfer

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23
Q

Coenzyme: cobalamin (B12)

A

alkylation

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24
Q

Coenzyme: THF

A

C1 (one-carbon) unit transfer

25
Q

THF - active form of

A

folic acid

• we don’t make it but in green vegetables and sythesized by bacteria

26
Q

Uses of the C1 pool

A

utilization of carbon in all different states

27
Q

Uses of the C1 pool:

N5,N10-Methylene-THF

A

dUMP –> dTMP

28
Q

Uses of the C1 pool:

N10-Formyl-THF

A

synthesis of purines

29
Q

Uses of the C1 pool:

N5-Methyl-THF

A
  • homocysteine –> methionine (not a productive reaction)
  • poor at transferring methyl group
  • converted to SAM (hangs on to anything, not very selective, because is high energy structure so transfers methyl to any acceptor)
30
Q

S-Adenosylmethionine (SAM)

A
  • more reactive (than N5-Methyl-THF that makes it)
  • readily passes on methyl group
  • in the process eventually converted back to methionine

Homocysteine + N5-Methyl-THF

–>

Methionine + THF

= only way back into C1 pool

• creates the activated methyl cycle

31
Q

Uses of the C1 pool:

Sulphonamides

A
  • antibiotics
  • structural unit similar to p-Aminobenzoic acid (p-ABA)
  • bacteria synthesize folic acid
  • sulphonamides inhibit p-ABA inclusion
  • can cause certain types of anemia
32
Q

Uses of the C1 pool

A

Vitamin B12

33
Q

Vitamin B12 structure

A
  • 1964 D Hodgkin
  • contains cobalt
  • co coordinated to tetrapyrrole ring system - corrin ring similar to haem
  • ring group forms equatorial ligands
34
Q

Vitamin B12 structure - Axial ligands

5th

A

heterocyclic base (sugar phosphate ring)

5,6-Dimethylbenzimaidazole (DMB)

• through sugar and phosphate to the equatorial ring

35
Q

Vitamin B12 structure - Axial ligands

6th

A

a cyano group

  • isolated –> CN
  • tissue –> H2O or OH-
36
Q

Vitamin B12 coenzyme forms

A
  • adenine - 5’-adenosylcobalamin
  • methyl - methylcobalamin
37
Q

Uptake/storage of Vitamin B12

A
  • made by bacteria
  • animals - derived from diet (meat, because we can’t make it ourselves)
  • stored in liver
  • use about 3migrograms daily
  • store about 3-5 years supply in liver (huge abundance to use but we have huge difficulty getting it into our bodies)
38
Q

Uses of Vitamin B12 coenzymes 3 uses

A
  • ribonucleotides –> deoxy form
  • intramolecular rearrangements
  • methylation
39
Q

Uses of Vitamin B12 coenzymes

Methylations

A

• THF regeneration in methionine synthesis

homocysteine + N5-Methyl-THF

–>

methionine + THF

  • enzyme: homocysteine methyl transferase aka methionine synthase
  • this enzyme is B12 dependent
40
Q

Vitamin B12 diseases

A
  • pernicious anemia (Vitamin B12 deficiency)
  • megaloblastic anemia (folate deficiency)
41
Q

Vitamin B12 diseases

absorption

A
  • body absorbs vitamin B12 poorly
  • absorption promoted by intrinsic factor (IF)
  • glycoprotein secreted by gut = can take B12 from gut into body, physical transport
  • when IF low –> pernicious anemia
42
Q

Vitamin B12 diseases pernicious anemia

A
  • when intrinsic factor (IF) low
  • autoimmune disease, may attack IF and knock it out of the gut so B12 can’t be absorbed
  • deficiency somewhere in B12 metabolism
  • very slow onset because we use such a small amount daily
  • begins with megaloblastic anemia (MA)
43
Q

Vitamin B12 diseases megaloblastic anemia

A
  • identical in appearance to folate deficiency initially
  • coenzyme B12 goes to a low concentration
  • lowers methionine synthase activity

(homocysteine + N5-Methyl-THF –> methionine + THF)

  • N5-Methyl-THF levels go up
  • imbalance occurs in C1 pool which diminishes all other THF-based reactions
  • folate involved in making RBC (hence anemia) - given to pregnant women so no anemia in babies
44
Q

Treatment of megaloblastic anemia

A
  • folate deficiency from low in diet –> eat more in diet
  • drug-induced –> alter drug regime
45
Q

Treatment of pernicious anemia

A

• Vitamin B12 deficiency from low IF

–> more in diet as supplement

–> sometimes actual B12 injections needed

46
Q

B12 and propionyl CoA general

A

propionyl CoA –> (rearrrangement by B12)

Succinyl CoA –>

citric acid cycle

47
Q

B12 and propionyl CoA specific

A

propionyl CoA –>

(carboxylation - carboxylic acid added)

(ATP hydrolysis - ATP –> ADP + Pi)

D-methylmalonyl CoA –>

(D isomer racemized to L isomer)

L-methylmalonyl CoA –>

(intramolecular rearrangement/isomerization)

succinyl CoA –>

citric acid cycle

• catalyzed by methylmalonyl CoA mutase with a derivative of B12 (cobalamin) as its coenzyme)

48
Q

Methionine –> SAM (+ Pi + PPi)

A
  • ATP gives adenosyl to sulfur atom of methionine
  • synthesis of SAM is unusual because the triphosphate group of ATP is split into pyrophosphate and orthophosphate
49
Q

SAM –>

A

• transfers methyl group to acceptor –>

forms S-Adenosylhomocysteine

• S-adenosylhomocysteine hydrolyzed to homocysteine and adenine SAM –>

(transfers methyl group to acceptor) S-adenosylhomocysteine–>

(hydrolysis, H2O in, adenosine out) homocysteine

50
Q

Methionine can be regenerated by

A

the transfer of a methyl group to homocysteine from N5-Methyl-THF

  • catalyzed by methionine synthase AKA homocysteine methyltransferase
  • coenzyme that mediates the transfer of a methyl group is methylcobalamin - derived from vitamin B12
51
Q

Methionine from homocysteine

A

homocysteine + N5-Methyl-THF

–> (transfer of methyl group to homocysteine from N5-Methyl-THF)

Methionine + THF

52
Q

Activated methyl cycle

A

• the methyl group of methionine is activated by the formation of SAM

SAM –>

(Active methyl CH3 out)

S-adenosylhomocysteine –>

(H2O in)

Homocysteine –>

(methyl CH3 in) Methionine –>

(ATP in) back to SAM

53
Q

The methyl of the activated methyl cycle

A

methyl enters in the conversion of homocysteine into methionine, then made highly reactive by addition of adenosyl group - which makes the sulfur atoms (+) charged and the methyl groups are more electrophilic

• the high transfer potential of the S-methyl group enables it to be transferred to a wide variety of acceptors)

54
Q

Tetrahydrofolate = cofactor 3 components

A
  • pteridine ring
  • p-aminobenzoate
  • 1 or more glutamate residues
55
Q

Most reduced oxidation state

A
  • oxidation state = methanol
  • CH3
  • name = methyl
56
Q

Intermediately reduced oxidation state

A
  • oxidation state = formaldehyde
  • CH2
  • name = methylene
57
Q

Most oxidized oxidation state

A
  • oxidation state = formic acid
  • CHO = formyl
  • CHNH = formimino
  • CH=(double bond) = methenyl
58
Q

Activated methyl cycle

A

Metabolic Pathways (11 decks)

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