Abstract
Three ADA (adenosine deaminase) inhibitors, DHMPR (1,6-dihydro-6-hydroxymethyl purine ribonucleoside); EHNA [erythro-9-(2-hydroxy-3 nonyl)adenine] ; and deoxycoformycin [(R)-3-(2-deoxy-β-d-erythro-pento-furanosyl)-3, 6,7,8-tetrahydroimidazo[4,5-d] [1,3-diazepin-8-ol] or Covidarabin, were compared with regard to their inhibitory behavior with ADAs from human erythrocytes and calf intestine. Marked differences in the times required for establishment of steady state between the enzyme and inhibitors were observed, e.g. DHMPR, virtually instantaneous; EHNA, 2-3 min; and deoxycoformycin, many hr. The parameters of the inhibition of human erythrocytic ADA by deoxycoformycin were as follows: the association rate constant (k1) = 2.6 × 106 M-1 sec-1 ; the dissociation rate constant of the enzyme-inhibitor complex (k2) = 6.6 × 10-6 sec-1; Ki (from k2 k1) = 2.5 × 10-12M and Ki (from I50) = 1.5 × 10-11 M. The Ki values for EHNA and DHMPR, as determined by classical methods after attainment of steady state, were 1.6 × 10-9 and 1.3 × 10-6 M, respectively, for human erythrocytic ADA. The kinetic parameters for EHNA and calf intestinal ADA were as follows: Ki = 6.5 × 10-9 M (by the method of I50); k1 = 0.7 × 106 M-1 sec-1' and k2 = 4.6 × 10-3 sec-1. On the basis of Ki values, the inhibitors. DHMPR, EHNA and deoxycoformycin (a transition state analog), were classified as readily reversible, semi-tight-binding and tight-binding inhibitors. The difficulties encountered in the kinetic analyses of different types of inhibitors and the methods for dealing with the problems of these inhibitors are discussed.
| Original language | English |
|---|---|
| Pages (from-to) | 359-367 |
| Number of pages | 9 |
| Journal | Biochemical Pharmacology |
| Volume | 26 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 1977 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Pharmacology
Cite this
Tight-binding inhibitors-IV. Inhibition of adenosine deaminases by various inhibitors. / Agarwal, Ram P.; Spector, Thomas; Parks, Robert E.
In: Biochemical Pharmacology, Vol. 26, No. 5, 01.03.1977, p. 359-367.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tight-binding inhibitors-IV. Inhibition of adenosine deaminases by various inhibitors
AU - Agarwal, Ram P.
AU - Spector, Thomas
AU - Parks, Robert E.
PY - 1977/3/1
Y1 - 1977/3/1
N2 - Three ADA (adenosine deaminase) inhibitors, DHMPR (1,6-dihydro-6-hydroxymethyl purine ribonucleoside); EHNA [erythro-9-(2-hydroxy-3 nonyl)adenine] ; and deoxycoformycin [(R)-3-(2-deoxy-β-d-erythro-pento-furanosyl)-3, 6,7,8-tetrahydroimidazo[4,5-d] [1,3-diazepin-8-ol] or Covidarabin, were compared with regard to their inhibitory behavior with ADAs from human erythrocytes and calf intestine. Marked differences in the times required for establishment of steady state between the enzyme and inhibitors were observed, e.g. DHMPR, virtually instantaneous; EHNA, 2-3 min; and deoxycoformycin, many hr. The parameters of the inhibition of human erythrocytic ADA by deoxycoformycin were as follows: the association rate constant (k1) = 2.6 × 106 M-1 sec-1 ; the dissociation rate constant of the enzyme-inhibitor complex (k2) = 6.6 × 10-6 sec-1; Ki (from k2 k1) = 2.5 × 10-12M and Ki (from I50) = 1.5 × 10-11 M. The Ki values for EHNA and DHMPR, as determined by classical methods after attainment of steady state, were 1.6 × 10-9 and 1.3 × 10-6 M, respectively, for human erythrocytic ADA. The kinetic parameters for EHNA and calf intestinal ADA were as follows: Ki = 6.5 × 10-9 M (by the method of I50); k1 = 0.7 × 106 M-1 sec-1' and k2 = 4.6 × 10-3 sec-1. On the basis of Ki values, the inhibitors. DHMPR, EHNA and deoxycoformycin (a transition state analog), were classified as readily reversible, semi-tight-binding and tight-binding inhibitors. The difficulties encountered in the kinetic analyses of different types of inhibitors and the methods for dealing with the problems of these inhibitors are discussed.
AB - Three ADA (adenosine deaminase) inhibitors, DHMPR (1,6-dihydro-6-hydroxymethyl purine ribonucleoside); EHNA [erythro-9-(2-hydroxy-3 nonyl)adenine] ; and deoxycoformycin [(R)-3-(2-deoxy-β-d-erythro-pento-furanosyl)-3, 6,7,8-tetrahydroimidazo[4,5-d] [1,3-diazepin-8-ol] or Covidarabin, were compared with regard to their inhibitory behavior with ADAs from human erythrocytes and calf intestine. Marked differences in the times required for establishment of steady state between the enzyme and inhibitors were observed, e.g. DHMPR, virtually instantaneous; EHNA, 2-3 min; and deoxycoformycin, many hr. The parameters of the inhibition of human erythrocytic ADA by deoxycoformycin were as follows: the association rate constant (k1) = 2.6 × 106 M-1 sec-1 ; the dissociation rate constant of the enzyme-inhibitor complex (k2) = 6.6 × 10-6 sec-1; Ki (from k2 k1) = 2.5 × 10-12M and Ki (from I50) = 1.5 × 10-11 M. The Ki values for EHNA and DHMPR, as determined by classical methods after attainment of steady state, were 1.6 × 10-9 and 1.3 × 10-6 M, respectively, for human erythrocytic ADA. The kinetic parameters for EHNA and calf intestinal ADA were as follows: Ki = 6.5 × 10-9 M (by the method of I50); k1 = 0.7 × 106 M-1 sec-1' and k2 = 4.6 × 10-3 sec-1. On the basis of Ki values, the inhibitors. DHMPR, EHNA and deoxycoformycin (a transition state analog), were classified as readily reversible, semi-tight-binding and tight-binding inhibitors. The difficulties encountered in the kinetic analyses of different types of inhibitors and the methods for dealing with the problems of these inhibitors are discussed.
UR - http://www.scopus.com/inward/record.url?scp=0017360775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0017360775&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(77)90192-7
DO - 10.1016/0006-2952(77)90192-7
M3 - Article
C2 - 849330
AN - SCOPUS:0017360775
VL - 26
SP - 359
EP - 367
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 5
ER -