1

BIOXHEIA T

1.

, , , . .

. ( ) . () .

, :

) , ' , ,

) , (messengers), .

, . , . (.1): ) , . () ' , .. ) , . ( ) ' , .. ) ( ) ( , ) .. ) () .. .

. , "" (signal) - . . (, )

2

"" 1904 William Bayliss & Ernest Starling , .

, , :

) / ) ) .

. , ,

, , .

, , . , , ( , -) (signal transduction) . , , , .

2.

:

) (.. ) ) (.. ) ) (.. ) )

(.. ).

, , ( , , , , , , ). .2 .3 "" . -. . / . , , (cascade): ng, , g (.3), , mg (.3) (.3).

3

() (. .26)

3. . () , () , ()

.3, , , , . .1, , .

1.

/

--5--

( )

(CRF CRH )

(GnRF GnRH)

(PRF)

(GRH)

(SIF)

(TRH)

(41 )

(10 )

(40 44 )

(14 28 ) (3 )

ACTH

- LH, FSH

GH

A GH ,TSH TSH, -

() (, ADH)

O

(MSH)

(LPH)

(

.,ACTH) (GH) (TSH)

(LH)

(FSH)

(9 ) (9 )

SH (13 ) SH (18 ) SH (12 ) LPH (93 ) LPH (60 ) (39 )

(191 ) (197 ) . 2 - (:96, :112 .) .2 . (:96, :121 ) .2 . (:96,:120 )

, , 2 ( 2 )

,

: : : , -

, :

, (4, 3)

I (.3.2.2)

(32 )

Ca 2+, Pi . ()

(37 )

Ca 2+, Pi

(.3.3) (.. )

(.. )

()

()

(. 3.2)

, , , - . , -

4

/ ( -)

( -)

(2 21

30 ,.3.1.1) (29 )

(36 )

(14 )

,,

,

,

-

()

()

()

( )

(-

,)

()

() 1 .(2 134,116 .)

,

- , , - . , - . FSH

,

2 (:96,:147 .)

2 (22 32 .)

LH

(, pH

6

3.

3.1

3.1.1

. , . ' , , , , . , , - - ( ), 20-30 , , . - , () . - (), (signal-peptidase) - (.. ) , , Golgi, . , , , , (, ).

, , . .4.

-

-

-

4.

7

, . 1922 Banting Best . 1955, Fred Sanger. H , , (.5).

20 Steiner (, ) , ( C) . mRNA , mRNA - - (23 ), . .5 () ().

5. () . () .

8

mRNA . , , . .

3.1.2

. (POMC), 8 (ACTH), -, -, - (-, ) (.6). ( ), -, , - () - (L). () (Arg-Lys, Lys-Arg, Lys-Lys) (.6).

- , . , , .

6. ..

, , -, ( , ADH) - (. 7). O , , . - . (barorecepors) , . , , ( ) .

9

7. .

3.1.3

, , , (- -) - () (.6).

, TRH (Thyrotropin realeasing hormone, ) , TRH. , , , Gln-His-Pro-Gly. TRH , . TRH (.8).

8. TRH.

10

3.1.4

TRH ( ) (.8) . . , GnRH RH (.2).

2. .

3.1.5 ()

(TSH), (LH), (FSH) o (hCG) . (. .1)

3.2

3.2.1

,

. , , (, ) (DOPA) . ( ). 9. , ( ), 3,4- (DOPA), . , , . cAMP ( ). To , DOPA , DOPA- , L- L-

11

, . - (DBH) , . -- (),

. , S- S- .

9. : . B: .

( , chromaffin), ATP 4:1 . ( ) (.9). (stress) .

, Ca2+ "" ATP . (.3.3.1), . , ( M )

. 10 , , : CRH

12

, ACTH - . (. 3.3), , , (. 9). , (.. ) () . [ ].

10. , . [ = --, = , P = , CTH = ].

3.2.2

(4)

(3), .11, () (DIT). , ( 660 kDa), 75% .

.. , . . (.12).

11. 4 3

13

12. : () (). : 3 4 (=,TG=, L=, =)

3, 4

- :

) 20% 140 o yr 3,5-- o- 4:1. 22. -, 25:1,

+ (-2e) (-1e), . .13. ,

, , , .

13. -22

14

) ( DIT DIT) , , 3 4. , .

) . 3 4

SH (), (.12), TBG (Thyroxine Binding Globulin) .

.

3.3

3.3.1 C

(.14)

(1) () . (2) ( )

.

(3) (), (4) (, ), . (5) (, ) .

, . - .

(. 14)

, , ACTH , FSH, LH . , . - ( P450, . 3.3.2) (C- 20 C-22) , (.14 15).

15

14. .

(, ). () (CTH) , (LH) (FSH) . (. 14). cAMP . , , . . , (corticotrophin releasing hormone, CRH, . 1), . H CRH, , (ACTH) , , , (. .3). , CRH ( ), ACTH ( ) . (feed back control) (. . 7).

- (C27) . 15.

(C21)

3- 4,5- (C21) (C21), (C21) (C21),

16

(C19) (C18). . 12,

C-21 , , (). C-17 17-

15. .

17

3 2

. (), . 17- C-17 , .

.

3.3.2

. , (. . 27, 28). , ( ) (, ). ( ) . . : , , -1.6-, -6-

DNA . . +, Cl-, HCO - .

,

. . . , 17- .

18

21- ( ACTH CRH ), ACTH, . . , 5- .

3.3.3 450.

450 ( , CO 450nm) . 2 CO . :

DPH + H+ + O2 + RH NADP+

+ H2O + R-OH

R () (.. ), (.. ) (.. ).

. . 1, , . .

, 450

, ,

..

.

450-Fe3+ 450-Fe2+ ( NADPH), . () .

. 16 P450. P450 2 . FeO3+. H H , . NADPH ( ).

19

16. 450 NADPH

450 , , NADPH NADPH-- , FAD. , 450, (.17) ( ).

NADPH ++ FAD Fe2+ Fe3+ R+O2

() 450

NADP+

FADH2 Fe3+

Fe2+

ROH+H2O

17. 450 .

20

( ), DPH- P-450 ( FAD FMN ), (R) , 2 2 o ( . 18).

P450

1

e-

R

P450

NADPH 450

FAD FMN

RO 2

2

e

-

P450-R P450

O2

18. 450

3.3.4 D 1,25 - D3

ROH + H2O

1,25 (1,25(OH)2D3) D3 , 7-, . , 7- . D3 . , D3 (. 19). 25()D3, 1,25 ()2D3. (), , . 1,25()2D3 , . (.19).

21

19. 1,25 - D3

3.4 .

.

. (.. ). . , .

3.4.1

, . 2 (, )

22

. 2 (PLA2),

o C (PLC) , D (PLD) PLA2 (. 20). , , . 450. . 21. , , , (20:5) .

20. .

21. .

) . 22 G2 (PGG2) (PG). . PGG2 PGH2 PG

(TX) 2 (PGI2).

23

2 (PGH2) (.22), () . (COX). COX COX-1 , COX-2 . COX-2 . COX ( ) 15--9,11 , . ( ) PGG 15-- , PGH2 (. 22).

22. PGH2.

PGH2 (. 23):

PGE ( ) PGH2 PGE2 PGH1 PGE1. PGF- ( ) PGH2 PGF2a. PG- ( ) PGH2 PGI2. , TXA- ( ) PGH2 TXA2. PGH1 8,11,14- , .

,

PG : , (ther) F (Fosfat ) . , PGF2a

24

- . .

23. PGH2 .

) . , , , . 5-, 8-, 12- 15- . 5- , (. 24). , - C5 5--

(5-HPETE). ( 4) 5-

4 (LTA4 ) . ( LTA4 ) LTA4 LTB4 LTC4 (-S-), LTC4.

-- (-) LTC4 LTD4 . LTD4 LTE4 .

LTC4, LTD4 LTE4 SRS-A (slow reacting substance of anaphylaxis).

, - () (. 24).

25

24. ( ).

3.4.2

(platelet activating factor, PAF)

1- --2--sn-3- 1--- 2--sn-3- (. 25). 2, 2- 1---2-- (-PAF). - , , -2 PAF.

PAF -PAF, 1---2--sn-3- (. 25).

26

25.

(PAF).

3.4.3.

-, (anandamide) 2-. CB1 CB2, , G, (. .11) , (. ). , , .

2- .

4.A

. , , , - Golgi . . , , , 2, . , , (.3.2.1), .

27

( 3.2.2) . , . () .

3

,

mRNA

mRNA

5.

H , , (.3). , ( ) (, down stream) . , .

. 26 . ( , ), (releasing hormone), ng. , (.3), - . ,

28

g, , g mg . , (half- life). , 1 . , . . 26, , ( , . .7).

26.

, : , , . .

29

5.1 ,

. . , , . 24 (circadian) / . :

ACTH (), (~8:00) , .

TSH

( )

( ) - . , , , .

28 -. . 27.

27: . .

(. 28).

30

28: .

(hCG).

6.

. , -

, 10-11-10-10 10-10-10-9 , . 5-100 5-10 . (binding carrier) . (.2). , , , . . (), - .

, , ().

"" (kd ~10-8-10-9 M). G (Thyroxin binding globulin), . , ( 7). . (..G), (S), (), . . , 0,02-0,04% .

, : )

) ) ) .

31

7.

(, feedback control), . , .

, ,

, , , .26, ( ). ( ) , . .

, . , , , (FSH) (LH). FSH , . , , () .

(, ), ( )

. (. . 26, 29). LH , (corpus luteum) (.29). (. 27, 29).

(), (CG), ( ). , (. 27, 29).

32

29. ( ) ( )

.

8.

(, half life) (.3). , . , .. R, GRH (.2) , . .. rg- , .

, TSH, LH, FSH, hCG,

, . , , . .

, ,

. (3.3.3), , ,

33

, , .

PAF , ( 1 ), , . o LTB4 , LTC4 LTD4 LTE4 .

, 2-AG .

9.

, , , , .

: ( ) , . (.27, 28, 29), , , .

, , Langerhans ( - ). ( Gs , .11) , cAMP (. ).

80-90mg/100mL. (.. ) ( stress ). , , ( , .11), , , . . ~80mg/100mL (. 30).

34

)

()

( )

- ()

()

( )

-

cAMP,

) ()

: , , . :

(internalization) (down regulation)

: DNA, RNA, ,

30. () (). ().

: . (-), (3.3.2). .

, .

10.

(signaling molecules), , , .

35

(.8.1), - . . . 30, , (,,), (,) , (), ().

, - , (.. , ).

31. .

10.1

, : (, binding) .

(receptors), ( , ), (, ), : ) ) (response). , . , , . .

:

1) (specificity)

36

d

2) (affinity) . (Kd)

3) 4) ,

5)

( , ), Van der Waals . , , . , , (insuline like growth factor I), .

, -

H + R HR :

[H ][ R]

[ HR]

k 2

k k1

( ) (1)

[] [R] , [HR] -. kd, -,

(affinity) . [R] = [HR] kd = [H] ( 50% ), kd. , , .

, 1/10 10 (kd).

( ), - (.32) , 9-91%.

()

()

()

32. .

37

, , Scatchard (Scatchard plot, 1947). , ( [B]/[F],[F]) . , , Scatchard .

Rt = ,

[Rt] = [HR] + [R] [R] = [Rt] - [HR]

(1) HR (ound hormone)

F (Free hormone), ,

[B]

[R]

(2)

[F ] Kd

[R] = [Rt] []

(2) [B]

[Rt ] [

B]

[B]

1

[ Rt ]

[F ] Kd [F ] Kd[ B] Kd

kd Rt (=-+) . 33. , ( kd ),

( =-1/ kd) . , , , [] / [F] 0 (.33) (capacity) .

33. Scatchard .

To , . ,

. 32, , .

38

(non specific binding) . (. 32).

, ( ) ( ). , , . , , . , , , . , , , , . 32, ().

10.1.1

, , Scatchard 33. . , , . Scatchard . .

Scatchard , .

10.1.2 .

%

. , . . , . . , , .

, 10% . () (spare

[ H ][ R] receptors). [HR]

Kd [] [R] [R]. [R] , . ,

39

. / .

10.1.3 . .

( ) . (up-regulation) (down- regulation), .

, , . (down-regulation) . ) . , . , , , (EGF), (PDGF). - , LDL , . , , . , (). , . EGF (half life) 30min , EGF. ) . , , . , cAMP, , .

40

11.

.15 Stryer (4 , ) . , .

.

i) G ( 7 , 7 )

: (AC): ( Gs) ( Gi) AMP (cAMP) ( , second messenger). (). C (PLC): 4,5- (2), (DAG, ) 1,4,5- (3, ). DAG

C (PKC), 3 Ca++

.

Ca++ .

2 (PL2): , , ( ) -. D (PLD), G: ( ), ( ), ( ).

ii) (GC), GMP (cGMP, ).

( ) cGMP.

iii) (RTK, receptor tyrosine kinase). : (1) RTK (.. ). (2) (- cross-phosphorylation) RTK (.. ). (3) JAK (Janus kinase) RTK (.. , )

.

(.. , ) , (nuclear hormone receptors). - DNA (control elements) .

41

Alberts B., Jonson A.,Lewis J, Raff M., Roberts K., Walter P., Molecular Biology of

the Cell, 4th

edition, Garland Science

Berg J.M., Tymoczko J.L. Stryer L. (2004) , 5 ,

Berg J.M., Tymoczko J.L., Stryer L. (2006) Biochemistry, 6th

edition

Burtis C., Ashwood E., (2001) Tietz Fundamentals of Clinical Chemistry, 5th

edition,

Saunders

Cooper J.R., Bloom F.E., Roth R.H. (1996) The Biochemical Basis of

Neuropharmacology, 7th

edition, Oxford University Press

Delvin T.M., ed (1992) Textbook of Biochemistry with Clinical Correlations, 3rd

edition, Wiley-Lis

Garett R.H, Grisham C.M. (2005) Biochemistry, 3rd

edition

Gurr M.I., Harwood J.L., Frayn K.N. (2002) Lipid Biochemistry An Introduction, 5th

edition, Blackwell Publishing

Lodish H., Baltimore D., Berk A., Zipursky S., Matsudaira P., Darnell J. (1999)

Molecular Cell Biology, 4th

edition, Freeman

Mathews C.K., van Holde K.E., Ahern K.G. (2000) Biochemistry, 3rd

edition,

Addison Wesley Longman

Zubay G., (1993) Biochemistry, 3rd

edition, Wm.C.Brown Publishers