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Insulin
• Polypeptide hormone produced by pancreatic
beta cells that regulates carbohydrate
homeostasis. Converted by proteolysis from the
single chain proinsulin, q.v., to the active dimer
composed of 51 amino acid residues; mol wt ~
6000. Regulates carbohydrate and lipid
metabolism, and influences protein synthesis.
Insulin was the first protein for which the
chemical structure and mol wt were determined.
Insulins
Gly
Ile
Val
CHAIN A
Glu
Gln–Cys–Cys–Thr–Ser–Ile–Cys–Ser–Leu–Tyr–Gln–Leu–Glu–Asn–Tyr–Cys–Asn
His–Leu–Cys–Gly–Ser–His–Leu–Val–Glu–Ala–Leu–Tyr–Leu–Val–Cys
Gln
Gly
CHAIN B
Asn
Glu
Val
Arg
Phe
Thr–Lys–Pro–Thr–Tyr–Phe–Phe–Gly
HUMAN INSULIN
Carbon - Red
Oxygen - Green
Nitrogen - Blue
Sulfur - Pink
Insulin
• Mechanism of Action
• The primary activity of insulin, is regulation of
glucose metabolism. Insulin and its analogs
lower blood glucose levels by stimulating
peripheral glucose uptake, especially by skeletal
muscle and fat, and by inhibiting hepatic glucose
production. Insulin inhibits lipolysis in the
adipocyte, inhibits proteolysis, and enhances
protein synthesis.
Insulins
А-верига
В-верига
8
9
10
30
Човешки THR SER
ILE
THR
Говежди ALA
Свински
SER
VAL
ALA
THR SER
ILE
ALA
Insulin glulisine injection
Insulin glulisine is produced by
recombinant DNA technology
utilizing a non-pathogenic
laboratory strain of Escherichia
coli (K12).
Insulin glargine is a human insulin analog that has been
designed to have low aqueous solubility at neutral pH.
Insulin glargine differs from human insulin in
that the amino acid asparagine at position
A21 is replaced by glycine and two
arginines are added to the C-terminus of
the B-chain. Chemically, it is 21 A -Gly-30
B a-L-Arg-30 B b-L-Arg-human insulin and
has the empirical formula C 267 H 404 N
72 O 78 S 6 and a molecular weight of
6063.
Gly
Ile
Val
C 21
CHAIN A
GLY
Glu
Gln–Cys–Cys–Thr–Ser–Ile–Cys–Ser–Leu–Tyr–Gln–Leu–Glu–Asn–Tyr–Cys–Asn
His–Leu–Cys–Gly–Ser–His–Leu–Val–Glu–Ala–Leu–Tyr–Leu–Val–Cys
Gly
Gln
CHAIN B
Asn
Glu
Val
Arg
Phe
ARG
ARG
Thr–Lys–Pro–Thr–Tyr–Phe–Phe–Gly
HUMAN INSULIN
Insulin aspart
NovoLog is homologous with regular human
insulin with the exception of a single
substitution of the amino acid proline by
aspartic acid in position B28, and is
produced by recombinant DNA technology
utilizing Saccharomyces cerevisiae
(baker's yeast) as the production
organism. Insulin aspart has the empirical
formula C256H381N65079S6 and a
molecular weight of 5825.8.
APIDRA™ (insulin glulisine [rDNA origin]) is a human insulin analog that is a rapid-acting,
parenteral
blood glucose lowering agent. Insulin glulisine is produced by recombinant
DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12).
Insulin glulisine differs from human insulin in that the amino acid asparagine at
position B3 is replaced by lysine and the lysine in position B29 is replaced by
glutamic acid. Chemically, it is 3B-lysine-29B-glutamic acid-human insulin,
has the empirical formula C258H384N64O78S6 and a molecular weight of 5823.
It has the following structural formula:
LEVEMIR® (insulin detemir [rDNA origin] injection) is a sterile solution
of insulin detemir for use as an injection.
Insulin detemir is a long-acting basal insulin analog, with up to
24 hours duration of action, produced by a process
that includes expression of recombinant DNA in Saccharomyces cerevisiae followed
by chemical modification. Insulin detemir differs from human insulin in that the
amino acid threonine in position B30 has been omitted, and a
C14 fatty acid chain has been attached to the amino acid B29.
Insulin detemir has a molecular formula of C267H402O76N64S6
and a molecular weight of 5916.9. It has the following structure:
Humalog (insulin lispro, rDNA origin) is a human insulin analog that
is a rapid-acting,
parenteral blood glucose-lowering agent. Chemically, it is Lys(B28),
Pro(B29) human insulin analog,
created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed.
Humalog is synthesized in a special non-pathogenic
laboratory strain of Escherichia coli bacteria that has been genetically altered
by the addition of the gene for insulin lispro.
Humalog has the following primary structure:
Cerezyme ® (imiglucerase for injection) is an analogue of the human enzyme,
(beta)-glucocerebrosidase produced by recombinant DNA technology.
(beta)-Glucocerebrosidase ((beta)-D-glucosyl-N-acylsphingosine glucohydrolase,
E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme which catalyzes
the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide.
Cerezyme ® is produced by recombinant DNA technology using mammalian cell culture
(Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein
of 497 amino acids, containing 4 N-linked glycosylation sites (Mr = 60,430).
Imiglucerase differs from placental glucocerebrosidase by one amino acid at position
495 where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation
sites have been modified to terminate in mannose sugars. The modified carbohydrate structures
on imiglucerase are somewhat different from those on placental glucocerebrosidase.
These mannose-terminated oligosaccharide chains of imiglucerase are specifically
recognized by endocytic carbohydrate receptors on macrophages,
the cells that accumulate lipid in Gaucher disease.
Пептиди
Биосинтетични:
Cyclosporin A immunosuppressant
Fermentation of Tolypocladium inflatum
H3C
H
CH3
OH
H
CH3
MeLeu–MeVal
N
O
C
C
Abu–MeGly
H
MeLeu– D-Ala–Ala–MeLeu–Val–MeLeu
Cyclosporin A
Interferons immunostimulants
Products from cells which contain
recombinant DNA
Hepatitis B vaccine (recimbinant DNA)
Синтетични пептиди: Captopril, Enalapril,
Lisinopril, Ramipril - antihypertonics
Ramipril
H3C
O
O
HOOC
CH3
H
N
NH
O
H
[2 S ,3a S ,6a S ]-1-[(2 S )-2-[[(1 S )-(Ethoxy carbonyl)3-phenylpropyl]amino]-1-oxopropyl]
octahydrocyclopenta[ b ]pyrrole-2-carboxylic acid
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3carboxylic acid derivative. It is a white, crystalline
substance soluble in polar organic solvents and
buffered aqueous solutions. Ramipril melts
between 105°C and 112°C.
Its empiric formula is C23H32N2O5, and its molecular
weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a
non-sulfhydryl angiotensin converting enzyme
inhibitor. Ramipril is converted to ramiprilat by
hepatic cleavage of the ester group.
Altace (ramipril) is supplied as hard shell capsules
for oral administration containing 1.25 mg, 2.5 mg,
5 mg, and 10 mg of ramipril. The inactive
ingredients present are pregelatinized starch NF,
gelatin, and titanium dioxide. The 1.25 mg capsule
shell contains yellow iron oxide, the 2.5 mg
capsule shell contains D&C yellow #10 and FD&C
red #40, the 5 mg capsule shell contains FD&C blue
#1 and FD&C red #40, and the 10 mg capsule shell
contains FD&C blue #1.
CH3
H2N
N(C2H5)3
COOCH2C6H5
O
CH3
O
COOC2H5
N
H
C2H5OOC
COOCH2C6H5
H
H2/Pd
COOCH2C6H5
C
NH
CH3
C2H5OOC
N
H
COOH
H
H3C
1
C2H5
2
O
P
H2/Pd
Ramipril
2
C
Enalapril
maleate
H3C
O
O
HOOC
CH3
N
NH
O
Vasotec is the maleate salt of enalapril, the ethyl ester
of a long-acting angiotensin converting enzyme inhibitor,
enalaprilat. Enalapril maleate is chemically described as
(S)-1-[N-[1-(ethoxycarbonyl) -3-phenylpropyl]-L-alanyl] -L-proline,
(Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5·C4H4O4.
Enalapril maleate is a white to off-white, crystalline powder
with a molecular weight of 492.53. It is sparingly soluble in water,
soluble in ethanol, and freely soluble in methanol.
Enalapril is a pro-drug; following oral administration,
it is bioactivated by hydrolysis of the ethyl ester to enalaprilat,
which is the active angiotensin converting enzyme inhibitor.
Enalapril maleate is supplied as
2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration.
In addition to the active ingredient enalapril maleate,
each tablet contains the following inactive ingredients:
lactose, magnesium stearate, starch, and other ingredients.
The 2.5 mg, 10 mg and 20 mg tablets also contain iron oxides.
HOOC
COOHCH3
N
NH
¥
2H O
2
O
VASOTEC * I.V.(Enalaprilat) is a sterile aqueous solution
for intravenous administration. Enalaprilat is an
angiotensin converting enzyme inhibitor.
It is chemically described as (S)-1-[N-(1-carboxy-3-phenylpropyl)L-alanyl]-L-proline dihydrate. Its empirical formula is C18H24N2O5•2H2O.
Enalaprilat is a white to off-white, crystalline powder
with a molecular weight of 384.43.
It is sparingly soluble in methanol and slightly soluble in water.
Each milliliter of VASOTEC I.V.contains 1.25 mg enalaprilat (anhydrous equivalent);
sodium chloride to adjust tonicity; sodium hydroxide to adjust pH;
water for injection, q.s.; with benzyl alcohol, 9 mg, added as a preservative
CH3
*
CH3
COCl2
*
OH
H2N
HN
O
O
HOOC
*
HOOC
HN
*
CH3
*
N
H2N
O
O
BzOOC
CH3
*
NH
P1
*
OH
O
DCC/CH2Cl2
HN
+
BzOOC
*
CH3
*
NH
P1
CF3COOH
N
O
BzOOC
HBr
or
NaOH
*
CH3
*
N
H2N
O
HOOC
*
CH3
*
H2N
O
N
H3C
O
O
1.
O
HOOC
*
CH3
*
N
H2N
O
2.
H2/Pd C
Enalapril
H11C6 N C N C6H11
33
RCOOH
H11C6NH
C
NC6H11
O
C R
O
33a
44
RCOO-H+
H11C6NH C
O
52
NC6H11
C R
O
O
R
C
O
53
C
R
N(CH3)2
O
(DMAP)
N
N(CH3)2
R1OH
DMAP
+
+
RCOOR1
55
N
C
R
O
54
RCOO-