How exactly does Finasteride inhibit Type II 5AR?

[Britannia]

Does it bind with the active site of the enzyme molecules? Or does it de-nature the enzyme?

 

[Aplunk1]

I would assume the latter because of the "diction" that Merck uses. They use the word "inhibit," which probably means de-nature the enzyme itself.

Am I crazy? I'm probably wrong anyway.

 

[Weepy]

Does it bind with the active site of the enzyme molecules? Or does it de-nature the enzyme?

It binds the active site. It is a competitive inhibitor.

Curious, what made you think it would denature the enzyme?

 

[Dinzy]

Denaturing an enzyme is a really harsh action for a drug to accomplish and still be safe. Something that denatures a protein will most likely denature simmilar proteins, ie those with simmilar subgroups.

 

[Weepy]

I cannot think of a single drug that works by denaturing protein.

 

[Britannia]

I cannot think of a single drug that works by denaturing protein.

No sure what the exact drug is, but drugs that denature proteins are used in Oncology, specifically in non-solid tumor treatments. The question was asked purely because Im curious as to the possibilty of producing a drug which can specifically denature a given protein. The reason I asked about finasteride was simply because it was a drug I thought people on this forum would be informed on. Ive got a crazy idea that an effective treatment for Prion diseases (i.e. CJD, Fatal Familial Insomnia etc) could exist in the form of a protein de-naturing drug.

 

[Weepy]

I cannot think of a single drug that works by denaturing protein.

No sure what the exact drug is, but drugs that denature proteins are used in Oncology, specifically in non-solid tumor treatments.

Interesting. Didn't know that. Do you happen to have any further information?

Thanks,

 

[Britannia]

I cannot think of a single drug that works by denaturing protein.

No sure what the exact drug is, but drugs that denature proteins are used in Oncology, specifically in non-solid tumor treatments.

Interesting. Didn't know that. Do you happen to have any further information?

Thanks,

Yeah got some info on my computer at work. Ill see what I can grab off it and post it here.

 

[Dave001]

Finasteride is a mechanism-based ("suicide") inhibitor, which irreversibly inhibits (covalent bonding) 5alpha-reductase.

 

[Weepy]

It's a "suicide inhibitor"; i.e., it forms a covalent bond with the enzyme.

This is not denaturing.

 

[Dave001]

This is not denaturing.

No kidding.

 

[Weepy]

It's a "suicide inhibitor"; i.e., it forms a covalent bond with the enzyme.

This is not denaturing.

No kidding.

Britania spoke of denaturing drugs. You responded, "It's a suicide inhibitor." I said this is not denaturing. Here, you acknowledge your error. Thanks, Dave!

 

[Dave001]

Britania spoke of denaturing drugs. You responded, "It's a suicide inhibitor." I said this is not denaturing. Here, you acknowledge your error. Thanks, Dave!

Are you retarded? I was responding to the original post and thread title. If I were referring to denaturation, I would've said so, or quoted text that made such evident.

 

[Weepy]

It's a "suicide inhibitor"; i.e., it forms a covalent bond with the enzyme.

This is not denaturing.

No kidding.

Britania spoke of denaturing drugs. You responded, "It's a suicide inhibitor." I said this is not denaturing. Here, you acknowledge your error. Thanks, Dave!

Are you retarded? I was responding to the original post and thread title. If I were referring to denaturation, I would've said so, or quoted text that made such evident.

Thanks for clarifying.

 

[Bryan]

Does it bind with the active site of the enzyme molecules? Or does it de-nature the enzyme?

It binds the active site. It is a competitive inhibitor.

It binds the active site, but it's not a competitive inhibitor. Finasteride and dutasteride are both considered to be irreversible inhibitors of the 5a-reductase type 2 enzyme. However, dutasteride is indeed a competitive inhibitor of the type 1 version.

Bryan

 

[Weepy]

Does it bind with the active site of the enzyme molecules? Or does it de-nature the enzyme?

It binds the active site. It is a competitive inhibitor.

It binds the active site, but it's not a competitive inhibitor. Finasteride and dutasteride are both considered to be irreversible inhibitors of the 5a-reductase type 2 enzyme. However, dutasteride is indeed a competitive inhibitor of the type 1 version.

Bryan

No. This is taken from Merck's prescription insert.

"Finasteride is a competitive and specific inhibitor of Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into DHT."

http://www.propecia.com/finasteride/pro ... /index.jsp

 

[Bryan]

I guess they're using the word "competitive" in either a sloppy way, or a way that differs from how most researchers do, in that context.

Bryan

 

[Dave001]

http://dx.doi.org/10.1021/ja953069t

J. Am. Chem. Soc., 118 (10), 2359 -2365, 1996. 10.1021/ja953069t
Copyright © 1996 American Chemical Society

Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP-Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor

Herbert G. Bull,* Margarita Garcia-Calvo, Stefan Andersson, Walter F. Baginsky, H. Karen Chan, Dina E. Ellsworth, Randall R. Miller, Ralph A. Stearns, Raman K. Bakshi, Gary H. Rasmusson, Richard L. Tolman, Robert W. Myers, John W. Kozarich, and Georgianna S. Harris

Contribution from the Merck Research Laboratories, Rahway, New Jersey, 07065

Received September 6, 1995

Abstract:

Finasteride is employed in treatment of benign prostatic hyperplasia in man, where its target enzyme is steroid 5-reductase. It is a novel, potent mechanism-based inhibitor of the human prostate (type 2) isozyme. Although it is accepted as an alternate substrate and is ultimately reduced to dihydrofinasteride, this proceeds through an enzyme-bound NADP-dihydrofinasteride adduct. Finasteride is processed with a second-order rate constant, ki/Ki = 1 × 106 M-1 s-1, that approaches kcat/Km for reduction of testosterone, 3 × 106 M-1 s-1, and essentially every catalytic event is lethal (partition ratio <= 1.07). The membrane-bound enzyme-inhibitor complex formed from [3H]finasteride appears to release [3H]dihydrofinasteride with a half-life of 1 month at 37&deg; C (k = (2.57 ± 0.03) × 10-7 s-1), as identified by mass spectroscopy. The intermediate NADP-dihydrofinasteride adduct can be recovered intact by denaturation of the enzyme-inhibitor complex and has been purified. Free in solution, it likewise decomposes to dihydrofinasteride (half-life = 11 days). An extremely potent bisubstrate analog inhibitor, this NADP-dihydrofinasteride adduct binds to the free enzyme with a second-order rate constant equal to kcat/Km for turnover of testosterone and has a dissociation constant Ki 1 × 10-13 M. Finasteride is also a mechanism-based inhibitor of the human skin (type 1) isozyme, but it is processed with a much smaller second-order rate constant, ki/Ki = 3 × 103 M-1 s-1, which attenuates its activity against this isozyme in vivo. The mechanism explains the exceptional potency and specificity of finasteride in treatment of benign prostatic hyperplasia, and the concept may have application to other pyridine nucleotide-linked enzymes.