Cystathionine-β-synthase(CBS) Inhibition--Myricetin, St.John's Wort

2020

https://www.mdpi.com/2218-273X/10/5/697/htm

Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

 

표 5. CBS의 약리학적 억제제. 

 

CBS 대 CSE에 대한 억제제의 선택성도 논의됩니다

 

      Name                        IC50                                            Selectivity

	Aminooxyacetic acid	1–8.5 μM	The compound is a potent CBS inhibitor which works by reacting with its PLP prosthetic group. Although it is commonly referred to as a “CBS inhibitor”, it is an even more potent inhibitor of CSE (IC50: 1 µM)
	Benserazide	30 μΜ	Relatively potent CBS inhibitor that reacts with its PLP prosthetic group. It has some selectivity for CBS (CSE is inhibited 16% at 100 µM benserazide and 3-MST is inhibited 50% at 300 µM benserazide)
	2,3,4-Trihydroxy-benzylhydrazine	30 μΜ	It inhibits CBS by reacting with its PLP prosthetic group. It may be responsible for some of the CBS-inhibitory effect of benserazide in vivo. Its effect on CSE has not been tested
	3-Hydroxy-benzylhydrazine	60 µM	It inhibits CBS by reacting with its PLP prosthetic group. Its effect on CSE has not been tested. It is known to inhibit GABA-T and other PLP-dependent enzymes
	Disulfiram	Not a direct inhibitor	In yeast assays and in Down syndrome mice, it has biological effects consistent with cell-based CBS inhibition
	Hydroxylamine	20–400 μM	The compound inhibits CBS, but it inhibits CSE more potently (IC50: 5 µM)
	Copper (Cu2+)	0.2–10 µM	The assessment of true CBS-inhibitory potency is made difficult by the fact that it also reacts with H2S, the product of the CBS reaction measured in the assay
	NSC 67078 1,6-dimethyl-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-dione	12–30 µM	It preferentially inhibits CBS; it also inhibits CSE, but with lower potency (IC50: 30 µM)
	NSC11041	4 µM	Approximately equipotent on inhibitor of CBS and CSE (IC50 ~3–4 µM)
	Sikokianin C	3.1 µM	Potent CBS inhibitor; its potency on CSE is weaker (IC50: 40 µM)
	Tannic acid	40 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	Hypericin -St.John's Wort	3.1 µM	Potent CBS inhibitor; its potency on CSE is weaker (IC50: 40 µM)
	Caraphenol A	5.9 µM	Fairly potent CBS inhibitor; its potency on CSE is almost comparable (IC50: 12 µM)
	2′′,4′′-Di-O-(Z-p-coumaroyl) afzelin	6.2 µM	Potent CBS inhibitor; its potency on CSE is very weaker (IC50 > 400 µM)
	3′-Hydroxy-volkensiflavon	7.8 µM	Potent CBS inhibitor; its potency on CSE is very weaker (IC50 > 400 µM)
	Cupressuflavone	11.5 µM	Potent CBS inhibitor; its potency on CSE is very weaker (IC50 > 400 µM)
	Podocarpusflavone A	8.9 µM	Potent CBS inhibitor; its potency on CSE is very weaker (IC50 > 400 µM)
	Agathisflavone	17.1 µM	Potent CBS inhibitor; its potency on CSE is very weaker (IC50 > 400 µM)
	Tangeritin	IC25: 46 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	Myricetin	18.8 µM	Fairly potent CBS inhibitor; its potency on CSE is similar (IC50: 14.4 µM)
	Apigenin	83 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	12α-hydroxy-5-deoxydehydro-munduserone	56 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	Rutin	116 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	Fraxetin	134 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	CH004	0.6–1.7 µM	A highly potent CBS inhibitor, with some selectivity towards CBS over CSE (IC50 ~ 30 µM)
	6S	Ki = 48 µM	It inhibits CBS inhibitor via interacting with its PLP group. Its effect on other H2S-producing enzymes or other PLP-dependent enzymes has not been characterized
	Aurintricarboxylic acid	3–80 µM	CBS inhibitor with considerable potency; it is even more potent as a CSE inhibitor (IC50 0.6–3 µM)
	Hexachlorophene	60 µM	CBS inhibitor with average potency
	Trifluoroalanine	66 μΜ	It does not have a high potency as a CBS inhibitor, but it exhibits some selectivity for CBS over CSE (IC50 ~ 300 µM)
	JHU-8555	8–12 µM	Approximately equipotent on inhibitor of CBS and CSE, with some preference for CBS (IC50 ~ 10–25 µM)
	MBSEW03275	15 µM	It does not have a high inhibitory potency as a CBS inhibitor, but it does have some selectivity for CBS over CSE (IC50 ~ 200 µM)
	SP14311008	20 µM	Approximately equipotent on inhibitor of CBS and CSE, with some preference for CBS (IC50 ~ 40 µM for CSE)
	1,4-Naphtoquinone	35 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	2,4-Dinitrophenol	56 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	Piperine	61 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	Amiloride	89 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	MNP2-A6	83 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	MNP2-B7	87 µM	CBS inhibitor; its effect on other H2S producing enzymes has not been tested
	NP-014428	7.4 µM	Fairly potent CBS inhibitor; its potency on CSE is weaker (IC50: 62 µM)
	NP-003872	8.1 µM	Fairly potent CBS inhibitor; its potency on CSE is weaker (IC50: 122 µM)
	β-cyano-alanine	40% inhibition at 10 mM	The compound is a weak CBS inhibitor, but it is a potent inhibitor of CSE (IC50: 14 µM)
	“Compound #1” 3-MST inhibitor	25% inhibition at 100 µM	The compound was identified as a potent 3-MST inhibitor (IC50: 1.7 µM), but it also exerts a weak inhibitory effect on CBS and CSE

 

그림 1. 포유류의 유황 아미노산 대사 조절에서 CBS 및 기타 효소의 역할. 

 

식이 단백질에서 취한 필수 아미노산인 메티오닌(Met)은 메티오닌 아데노실트랜스퍼라제(MAT)에 의해 ATP와 축합되어 S-아데노실메티오닌(SAM)을 형성합니다. 

SAM은 다양한 메틸트랜스퍼라제(MT)에 의해 촉매되어 메틸화된 생성물 및 S-아데노실호모시스테인(SAH)을 생성하는 다중 메틸화 반응을 위한 보편적인 메틸 공여체 역할을 합니다. 

SAH는 이후 SAH 가수분해효소(SAHH)에 의해 아데노신과 호모시스테인(Hcy)으로 가수분해됩니다. 

그런 다음 Hcy는 두 경쟁 경로 사이에 배포됩니다. 

Met를 보존하기 위해 Hcy는 간 의존성 베타인 호모시스테인 메틸트랜스퍼라제(BHMT) 또는 유비쿼터스 메티오닌 합성효소(MS)의 작용에 의해 Met로 다시 재메틸화됩니다. 

Cys를 생성하기 위해 Hcy는 시스타티오닌 베타 합성효소(CBS)-세린(Ser)과의 축합에 의해 메티오닌 회로에서 황화환원 경로로 비가역적으로 전환되어 시스타티오닌(Cth)을 형성하고, 이는 후속적으로 시스타티오닌 감마 분해효소(CSE, 문헌에서 "CGL"이라고도 하는 효소)를 시스테인(Cys)으로 전환합니다. 

중요하게도, SAM은 CBS의 알로스테릭 활성화와 methylenetetrahydrofolate reductase(MTHFR)의 억제를 통해 경쟁 경로를 통해 Hcy의 흐름을 조절합니다. 

흥미롭게도, 황화경로의 모든 효소와 재메틸화(엽산 회로) 효소는 비타민 B 계열 구성원의 도움이 필요합니다.

B2 (riboflavin) in MTHFR,

B6 (pyridoxine) in serine hydroxymethyltransferase (SHMT), CBS and CSE,

B9 (folic acid) as a one-carbon carrier of the remethylation cycle, or

B12 (cobalamin) in MS.,

 

 

그림 8. 건강과 질병에서 세포 생존력의 조절에서 CBS 발현과 H 2 S 생합성 의 종 모양 역할 . 

 

CBS 억제는 암세포가 세포 보호 인자 및 생물 에너지 "연료"로 사용하는 H 2 S 의 형성을 감소시켜 암세포 생존 능력을 손상시킬 수 있습니다 . 

CBS 억제는 또한 예를 들어 다운 증후군에서 H 2 S 의 독성 과잉 생산을 정상화함으로써 세포 생존력을 향상시킬 수 있습니다 .