Transcript Phar 722 Pharmacy Practice III

Phar 722
Pharmacy Practice III
VitaminsBiotin
Spring 2006
Biotin Study Guide
• The applicable study guide items in the
Vitamin Introduction
• History
• Structure of the vitamin and cofactor
forms
• Function of the cofactor including
specific types of reactions catalyzed
• Deficiency condition
History
• 1916
– It was recognized that rats fed a diet high in raw
egg white exhibited muscle incoordination,
dermatitis and loss of hair.
• Cooked egg white was not toxic.
– The toxicities from the raw egg white could be
prevented by feeding liver or yeast to the animals.
– Deficiencies can be induced by a diet restricted to
raw egg white.
• 1942
– The biotin structure was published.
Biotin Chemistry
• Biotin consists of two 5-membered rings cisfused to each other.
• The d-isomer is the only active form.
H
O
O
N
HN
NH
H
H
H
Enolic form
H
H
O
O
(CH2)4
S
NH
OH
(CH2)4
S
H
Keto or ureido form
OH
Biotin Uptake and Metabolism
• Little is known about biotin uptake.
• There does not seem to be a cofactor form
different from the basic structure.
• The carboxyl chain forms an amide linkage
with the ε-amino nitrogen of lysine which
binds the vitamin to the enzyme's active site.
• Biotin is required for the addition of carbon
dioxide in many, but not all, carboxylation
reactions.
• There is some debate about the structure of
the cofactor intermediate that transfers the
carbon dioxide. See the next slide.
H
O
N
NH
H
H
S
Lys residue
O
(CH2)4
N
H
(CH2)4
CH
NH
Coenzyme form of Biotin
O
C
Addition of CO2 to biotin for subsequent carboxylation reactions.
O
-O
C
O
H
Bicarbonate
ATP
H
H
ADP
O
O
HO
O
P
C
Pi
O
H
O
C
N
C
NH
O
O
Phosphoric-carbonic acid anhydride
S
N
-O
H
H
-
O
O
O
NH
H
H
O
(CH2)4
Enz
S
O
(CH2)4
Enz
Biotin Function-1
• Methylmalonyl CoA from propionyl CoA
Val, Ile, Met, Thr
O
CH3
CH2
CSCoA
CO2
-O
Propionyl CoA
O
CH3
O
C
CH
C
SCoA
Methyl Malonyl CoA
cobalamin
O
-O
C
O
CH2
CH2
Succinyl CoA
C
SCoA
Biotin Function-2
• Oxalacetate from pyruvate (gluconeogenesis;
anapleurotic reactions)
CH3
O
O
C
C
Pyruvate
O
CO2
O-
-O
C
CH2
Oxalacetate
O
O
C
C
O-
Biotin Function-3
• Formation of carbamyl phosphate (urea cycle)
O
H2N
C
O
Carbamyl Phosphate
PO3
Biotin Function-4
• Malonyl CoA from acetyl CoA (fatty acid synthesis)
CH3
C
O
CO2
O
SCoA
Acetyl CoA
-O
C
O
CH2
C
Malonyl CoA
SCoA
Biotin Function-5
• Metabolism of leucine
Biotin Deficiency
• One of the ways to induce a deficiency in humans is
to feed the volunteer a raw egg white diet.
– Deficiency symptoms include hair loss, a rash around the
nose and mouth, and conjunctivitis.
• A good source of biotin is egg yolk.
– Therefore, eating whole raw eggs will not cause a deficiency
of this vitamin (although person could be at increased risk
for salmonella poisoning).
• What is the problem with raw egg white?
– Egg white contains a basic protein known as avidin which
forms salt linkages with the acidic biotin that might be in the
intestinal tract (possibly produced by intestinal bacteria?).
• This complex is not absorbed, but remains in the intestine
eventually to be excreted.
– Cooking the egg white ties up the avidin in the rest of the
egg albumin preventing its binding biotin.
Hypervitaminosis Biotin
• None has been reported in humans.
• There is no UL.
Dosage Forms
• The synthetic racemic mixture is used
commercially.
– As with racemic pantothenic acid and pantothenol,
only half of the racemic biotin is active.
• Biotin is considered one of the more expensive
vitamins and can add to the cost of the final
product.
• Solubility 0.3 -0.4 mg/ml (1 gm/2,500-3,300 ml)
DRIs
• AI
–
–
–
–
–
–
Infants
Children (1 - 13 years)
Adolescents (14 - 18 years)
Adults
Pregnancy
Lactation
• EAR
– None reported
• RDA
– None reported
• UL
– None reported
5 - 6 μg/day
8 - 20 μg/day
25 μg/day
30 μg/day
30 μg/day
35 μg/day
Sources
•
•
•
•
Liver
Kidney
Yeast
Animal and plant tissue in general;
• Possibly the intestinal bacteria