lecture 16: vitamin K

Question 1

vitamin K

Answer 1

fat-soluble vitamin, anti-hemorrhagic factor

cofactor in post-translational modification reaction

converting Glu residues to Gla residues which can bind Ca2+ (help bind Ca2+)
y-carboxylation of Glu residues to Gla

Question 2

ca2+

Answer 2

Ca2+ binding by clotting factors is essential for assembly of coagulation complexes on phospholipids at injury site in vessel wall

Question 3

phylloquinone (vitamin K1)

Answer 3

form of vitamin K isolated from green plants

Question 4

menaquinones (K2)

Answer 4

synthesized by bacteria

Question 5

absorption and transport

Answer 5

resembles that of cholesterol
circulating phylloquinone found in HDL, LDL, VLDL

Question 6

4 vitamin K-dependent clotting factors

Answer 6

prothrombin, factors VII, IX, X
shown to bind Ca2+ and bind to negatively charged phospholipid surfaces

Question 7

signal peptide (on vitamin K-dependent proteins)

Answer 7

penetration in ER lumen, N-terminal signal peptide removed by signal peptidase upon entering ER lumen

Question 8

propeptides & y-carboxylation

Answer 8

propeptides attached to vitamin K-dependent precursors are recognized by y-carboxylase in ER membrane
y-carboxylase anchors precursors for y-carboxylation of Glu, which requires vitamin K (KH2) as cofactor > becomes K>O via napthoquinone ring system
vitamin K-dependent proteins released, propeptide removed by furin in the golgi

Question 9

vitamin K cycle

Answer 9

Glu to Gla = KH2 to K>O
VKOR = K>O to KH2
KH2 oxidized in y-carboxylation rxn

Question 10

VKOR

Answer 10

reduce vitamin K from epoxide (K>O) to KH2
inhibited by warfarin (blood thinner)

Question 11

chemistry of vitamin K action

Answer 11

1) KH2 becomes a strong base via y-carboxylase
2) strong base vitamin K deprotonates y-carbon of Glu residue > Glu carbanion
3) CO2 + Glu carbanion = Gla

Question 12

DT-diaphorase

Answer 12

warfarin-insensitive
can reduce K to KH2 via NADH/NADPH but cannot reduce K>O

Question 13

warfarin

Answer 13

blood thinner/anticoag, inhibits VKOR and therefore regeneration of KH2 from K>O
does not inhibit y-carboxylase

Question 14

dicoumarol

Answer 14

responsible for hemorrhagic disease in cattle > use as first anticoagulant drug, but not clinically safe

Question 15

warfarin resistance

Answer 15

pharmacological resistance from high turnover of drug in liver by cytochrome P450 system

nutritional resistance from high vitamin K intake

Question 16

vitamin K & intestinal bacteria

Answer 16

produce menaquinones (K2) - human gut has a lot of bacterially produced vitamin K

slow turnover of K2 in liver
significant but K2 produces only a minor portion of vitamin K needed (cannot rely on gut microbes but it helps prevent deficiency)

Question 17

vitamin K deficiency

Answer 17

typically a low dietary intake plus antibiotics (interferes with K2 in the fut)