엔올레이스

3. 구조

엔올레이스는 엔올레이스 슈퍼패밀리에 속하는 효소이다. 분자량은 동질효소의 종류에 따라 82,000~100,000 Da이다.^[42][43] 활성 부위에는 2개의 Mg²⁺ 보조 인자가 있으며, 이는 기질의 음전하를 안정화시킨다.^[42][45]

최근에는 플라스미노겐과의 상호작용과 같은 엔올레이스의 문라이팅(moonlighting) 기능이 효소의 촉매 루프 및 구조적 다양성과 관련하여 주목받고 있다.^[46][47]

3. 1. 소단위체 구조

3. 2. 4차 구조

3. 3. 활성 부위

4. 메커니즘

엔올레이스는 2-포스포글리세르산(2-PG)을 포스포엔올피루브산(PEP)으로 전환하는 반응을 촉매한다. 이 반응은 카르보음이온 중간생성물을 포함하는 E1cB-제거 반응으로 제안된다.^[48]

4. 1. 반응 단계

4. 2. 입체구조 변화

5. 진단용

최근 의료 실험에서 엔올레이스 농도는 특정 질병과 그 심각성을 진단하는데 사용되었다. 뇌척수액에서 높은 농도의 엔올레이스는 별아교세포종과 강한 상관관계를 보였고,^[55] 뇌척수액 엔올레이스 수치가 높은 환자일수록 종양 성장 속도가 빨랐다. 심근 경색 또는 뇌졸중을 겪은 환자에게서도 엔올레이스 수치가 증가했다.^[56] α-엔올레이스에 대한 자가항체는 하시모토 뇌병증과 관련이 있다.^[58]

5. 1. 뇌척수액 엔올레이스

5. 2. 혈청 엔올레이스

5. 3. 자가항체

6. 저해제

엔올레이스 저해제는 효소의 촉매 메커니즘을 연구하고, 암과 같은 질병의 치료제를 개발하는 데 사용된다.^[59][60]

최근 활성 부위 전이 상태 유사 엔올레이스 억제제가 다양한 미생물 병원체 치료 및 ENO1 유전자 결손(1p36 동형 접합 결손) 종양에 대한 정밀 종양학 분야에서 전임상적으로 연구되고 있다.^{[31][35][36][37][38][39][40]}

SF2312의 유도체인 HEX와 이의 전구약물(프로드럭)인 POMHEX는 전임상 두개 내 정위 마우스 모델에서 ENO1 결손 신경교종에 대한 항종양 활성을 보였다.^[31]

6. 1. 작용 기전

6. 2. 주요 저해제

• 포스포노아세토하이드록사메이트: 가장 강력한 저해제 중 하나로, 양성자화되지 않은 형태로 효소에 대한 pM 친화도를 갖는다.^[62] 2-포스포글리세르산과 포스포엔올피루브산 사이에서 추정되는 촉매 중간생성물과 구조적으로 유사하다. 트리파노소마 치료제^[63] 및 항암제^[64]로 연구되고 있다. 특히 교모세포종과 같이 ENO1 유전자의 동형 접합 결실(합성치사)로 인해 엔올레이스가 결핍된 경우에 사용하려는 시도가 있었다.
• SF2312: 포스폰산 항생제로, 그람 양성 및 음성 세균에 대해 활성을 가지며, 특히 혐기성 조건에서 엔올레이스를 강력하게 저해한다.^[65][66] 포스포노아세토하이드록사메이트와 유사한 방식으로 결합한다. 진핵생물 및 원핵생물 기원의 엔올레이스 활성을 모두 억제한다.^[29] SF2312의 3S-에난티오머만 엔올레이스 억제 활성 및 생물학적 활성을 나타낸다.^[30]
• ENOblock: 알로스테릭 결합제로, 처음에는 엔올레이스 저해제로 알려졌으나, 실제로는 효소 분석을 방해하는 것으로 밝혀졌다.^[67] 이후 세포 및 동물 조직에서 엔올레이스 활성을 저해하는 것으로 확인되었다.^[69]
• 메틸글리옥살: 사람 엔올레이스의 저해제로 알려져 있다.^[70]
• 플루오린화물: 2-포스포글리세르산과 경쟁적으로 엔올레이스 활성 부위에 결합하여 효소 활성을 저해한다.^[43] 플루오린화물은 마그네슘 및 인산과 복합체를 형성하여 2-포스포글리세르산 대신 결합한다. 세균의 엔올레이스를 억제하여 충치 예방 효과를 나타낼 수 있다.^[71]

7. 슈퍼패밀리

엔올레이스는 엔올레이스 슈퍼패밀리의 대표적인 구성원이다. 이 슈퍼패밀리에는 만델산 라세미레이스 등 유사한 반응 메커니즘을 가지지만 다양한 기질에 작용하는 진화적으로 관련된 효소들이 포함된다.

참조

_[1] 논문 Mechanism of enolase: the crystal structure of asymmetric dimer enolase-2-phospho-D-glycerate/enolase-phosphoenolpyruvate at 2.0 A resolution 1997-10
_[2] 논문 Crystal structure of human beta enolase ENOB
_[3] 논문 Multifunctional alpha-enolase: its role in diseases 2001-06
_[4] 논문 Purification and properties of enolase of human erythrocytes 1974-11
_[5] 논문 Über die enzymatische umwandlung von phosphoglyzerinsäure in brenztraubensäure und phosphorsäure
_[6] 논문 Molecular structure of the human muscle-specific enolase gene (ENO3) 1991-04
_[7] 논문 Plasmin(ogen)-binding alpha-enolase from Streptococcus pneumoniae: crystal structure and evaluation of plasmin(ogen)-binding sites 2004-10
_[8] 논문 Crystal structure of an efficacious gonococcal adherence inhibitor: an enolase from Lactobacillus gasseri 2014-06
_[9] 논문 Isotopic probes of the enolase reaction mechanism
_[10] 논문 Toward identification of acid/base catalysts in the active site of enolase: comparison of the properties of K345A, E168Q, and E211Q variants 1996-02
_[11] 논문 Structural and mechanistic studies of enolase 1996-12
_[12] 논문 Octahedral coordination at the high-affinity metal site in enolase: crystallographic analysis of the MgII--enzyme complex from yeast at 1.9 A resolution 1995-04
_[13] 논문 Chelation of serine 39 to Mg2+ latches a gate at the active site of enolase: structure of the bis(Mg2+) complex of yeast enolase and the intermediate analog phosphonoacetohydroxamate at 2.1-A resolution 1994-08
_[14] 논문 A carboxylate oxygen of the substrate bridges the magnesium ions at the active site of enolase: structure of the yeast enzyme complexed with the equilibrium mixture of 2-phosphoglycerate and phosphoenolpyruvate at 1.8 A resolution 1996-04
_[15] 논문 X-ray structure and catalytic mechanism of lobster enolase 1995-10
_[16] 논문 Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathological change 1981-12
_[17] 논문 Neurological outcome after out-of-hospital cardiac arrest. Prediction by cerebrospinal fluid enzyme analysis 1989-07
_[18] 논문 Cerebrospinal fluid enolase in stroke 1984-07
_[19] 논문 Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase 2008-10
_[20] 논문 Autoantibodies against the amino terminal of alpha-enolase are a useful diagnostic marker of Hashimoto's encephalopathy 2005-05
_[21] 논문 Reaction intermediate analogues for enolase 1984-06
_[22] 논문 A unique small molecule inhibitor of enolase clarifies its role in fundamental biological processes 2013-04-02
_[23] 논문 Structure of the bis divalent cation complex with phosphonoacetohydroxamate at the active site of enolase 1992-08
_[24] 논문 Catalytic metal ion binding in enolase: the crystal structure of an enolase-Mn2+-phosphonoacetohydroxamate complex at 2.4-A resolution 1994-05
_[25] 논문 Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics 2007-10
_[26] 논문 Passenger deletions generate therapeutic vulnerabilities in cancer 2012-08
_[27] 논문 Studies on a new phosphonic acid antibiotic, SF-2312. 1986
_[28] 논문 SF2312 is a natural phosphonate inhibitor of enolase 2016-12
_[29] 논문 Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate 2019-11
_[30] 논문 The 3''S'' Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues 2019-07
_[31] 논문 An enolase inhibitor for the targeted treatment of ENO1-deleted cancers 2020-12
_[32] 논문 ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase 2016-12-28
_[33] 논문 ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes 2017-03
_[34] 논문 Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products 2009-04
_[35] 논문 Targeting Host Glycolysis as a Strategy for Antimalarial Development 2021-09-16
_[36] 논문 Structure-guided microbial targeting of antistaphylococcal prodrugs 2021-07
_[37] 논문 Antimicrobial Prodrug Activation by the Staphylococcal Glyoxalase GloB 2020-11
_[38] 논문 Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma 2020-10
_[39] 논문 Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate 2019-11
_[40] 논문 The 3''S'' Enantiomer Drives Enolase Inhibitory Activity in SF2312 and Its Analogues 2019-07
_[41] 논문 Isolation, characterization, and inhibition kinetics of enolase from Streptococcus rattus FA-1 1990-04
_[42] 논문 Multifunctional alpha-enolase: its role in diseases http://link.springer[...] 2001-06
_[43] 논문 Purification and properties of enolase of human erythroctyes
_[44] 문서 Über die enzymatische umwandlung von phosphoglyzerinsäure in brenztraubensäure und phosphorsäure (Enzymatic transformation of phosphoglyceric acid into pyruvic and phosphoric acid) 1934
_[45] 논문 Molecular structure of the human muscle-specific enolase gene (ENO3) 1991-04
_[46] 논문 Plasmin(ogen)-binding alpha-enolase from Streptococcus pneumoniae: crystal structure and evaluation of plasmin(ogen)-binding sites 2004-10
_[47] 논문 Crystal structure of an efficacious gonococcal adherence inhibitor: an enolase from Lactobacillus gasseri 2014-06
_[48] 논문 Isotopic probes of the enolase reaction mechanism
_[49] 논문 Toward identification of acid/base catalysts in the active site of enolase: comparison of the properties of K345A, E168Q, and E211Q variants 1996-02
_[50] 논문 Structural and mechanistic studies of enolase 1996-12
_[51] 논문 Octahedral coordination at the high-affinity metal site in enolase: crystallographic analysis of the MgII--enzyme complex from yeast at 1.9 A resolution 1995-04
_[52] 논문 Chelation of serine 39 to Mg2+ latches a gate at the active site of enolase: structure of the bis(Mg2+) complex of yeast enolase and the intermediate analog phosphonoacetohydroxamate at 2.1-A resolution 1994-08
_[53] 논문 A carboxylate oxygen of the substrate bridges the magnesium ions at the active site of enolase: structure of the yeast enzyme complexed with the equilibrium mixture of 2-phosphoglycerate and phosphoenolpyruvate at 1.8 A resolution 1996-04
_[54] 논문 X-ray structure and catalytic mechanism of lobster enolase 1995-10
_[55] 논문 Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathological change 1981-12
_[56] 논문 Neurological outcome after out-of-hospital cardiac arrest. Prediction by cerebrospinal fluid enzyme analysis 1989-07
_[57] 논문 Cerebrospinal fluid enolase in stroke 1984-07
_[58] 논문 Autoantibodies against the amino terminal of alpha-enolase are a useful diagnostic marker of Hashimoto's encephalopathy 2005-05
_[59] 논문 Reaction intermediate analogues for enolase 1984-06
_[60] 논문 A unique small molecule inhibitor of enolase clarifies its role in fundamental biological processes. 2013-04-02
_[61] 논문 Structure of the bis divalent cation complex with phosphonoacetohydroxamate at the active site of enolase 1992-08
_[62] 논문 Catalytic metal ion binding in enolase: the crystal structure of an enolase-Mn2+-phosphonoacetohydroxamate complex at 2.4-A resolution 1994-05
_[63] 논문 Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics 2007-10
_[64] 논문 Passenger deletions generate therapeutic vulnerabilities in cancer 2012-08
_[65] 논문 Studies on a new phosphonic acid antibiotic, SF-2312. 1986
_[66] 논문 SF2312 is a natural phosphonate inhibitor of enolase 2016-12
_[67] 논문 ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase. 2016-12-28
_[68] 논문 ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes. 2017-03-08
_[69] 논문 ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes. 2017-03-08
_[70] 논문 Inhibition of human muscle-specific enolase by methylglyoxal and irreversible formation of advanced glycation end products. 2009-04-29
_[71] 저널 Isolation, characterization, and inhibition kinetics of enolase from Streptococcus rattus FA-1 http://iai.asm.org/c[...] 1990-04