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

Glu

Val

Ile

Gly

Gln

Asn

Gly

Glu

Gln–Cys–Cys–Thr–Ser–Ile–Cys–Ser–Leu–Tyr–Gln–Leu–Glu–Asn–Tyr–Cys–Asn

Arg

His–Leu–Cys–Gly–Ser–His–Leu–Val–Glu–Ala–Leu–Tyr–Leu–Val–Cys

Thr–Lys–Pro–Thr–Tyr–Phe–Phe–Gly

Val

Phe

CHAIN A

CHAIN B

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 SER VAL ALA

Свински 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.

Glu

Val

Ile

Gly

Gln

Asn

Gly

Glu

Gln–Cys–Cys–Thr–Ser–Ile–Cys–Ser–Leu–Tyr–Gln–Leu–Glu–Asn–Tyr–Cys–Asn

Arg

His–Leu–Cys–Gly–Ser–His–Leu–Val–Glu–Ala–Leu–Tyr–Leu–Val–Cys

Thr–Lys–Pro–Thr–Tyr–Phe–Phe–Gly

Val

Phe

CHAIN A

CHAIN B

HUMAN INSULIN

ARGARG

GLY

C 21

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.

ПептидиБиосинтетични:

Cyclosporin A immunosuppressant

Fermentation of Tolypocladium inflatum

N

H

C

CH3

Abu–MeGlyMeLeu–MeVal

MeLeu–D-Ala–Ala–MeLeu–Val–MeLeu

H3C

CH3

OH

H

H

Cyclosporin A

C

O

Interferons immunostimulants

Products from cells which contain

recombinant DNA

Hepatitis B vaccine (recimbinant DNA)

Синтетични пептиди: Captopril, Enalapril,

Lisinopril, Ramipril - antihypertonics

Ramipril

NH

CH3O O

O

N

H3C HOOC

H

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-3-carboxylic 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.

COOC2H5

O

COOCH2C6H5

CH3

H2N

N(C2H5)3

N

O

C2H5OOCH

COOCH2C6H5

CH3

H2/Pd C

NC2H5OOCH

COOH

CH3NH

H

H

COOCH2C6H5

1 P

H3C

C2H5 2

O

2 H2/Pd C

Ramipril

Enalapril

maleate

HOOC

NH

CH3

O O

O

H3C

N

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.

¥ 2H2

O

HOOCCOOH

NH

CH3

O

N

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

O

OHH2N

*

COCl2

CH3

O

N

*

H2N*

HOOC

*

H

CH3 O

O

N

N

*

HOOC

H

NNH

CH3

O

OH

P1

BzOOC

H+

DCC/CH2Cl2

NH

CH3

OP1

N

BzOOC

*

*

CF3COOH

*

*

HBror

NaOH

CH3

O

N

*

H2N*

HOOC

CH3

O

N

BzOOC

*

*H2N

CH3

O

N

*

H2N*

HOOC

O OH3C

O

1.

2. H2/Pd C

Enalapril

RCOOH

H11C6 N C N C6H11

RCOO-H+

H11C6NH C NC6H11

O C R

O

H11C6NH C NC6H11

O

O C R

44

52

R C

O

O

O

N

N(CH3)2

R C

N

C

R

N(CH3)2

+

O

RCOO-

54

53

33

33a

R1OH

(DMAP)

RCOOR1+DMAP

55