(S)-Hmg-CoA

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (S)-Hmg-CoA
• 英文别名: (3S)-5-[2-[[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonatooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethyl-1-oxidobutylidene]amino]-1-oxidopropylidene]amino]ethylsulfanyl]-3-hydroxy-3-methyl-5-oxopentanoate
• 化学式: C27H39N7O20P3S-5
• 分子量: 906.6
• InChiKey: CABVTRNMFUVUDM-VRHQGPGLSA-I

计算性质

• 辛醇/水分配系数(LogP)：
  -6.3
• 重原子数：
  58
• 可旋转键数：
  22
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  461
• 氢给体数：
  6
• 氢受体数：
  25

反应信息

• 作为反应物：
  描述：

  (S)-Hmg-CoA 生成 acetoacetic acid anion 、 (2R)-N-[3-(2-acetylsulfanylethylimino)-3-oxidopropyl]-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonatooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanimidate
  参考文献：
  名称：

  禽类3-羟基-3-甲基戊二酰辅酶A裂解酶：酶活性对硫醇/二硫键交换的敏感性和近端反应性半胱氨酸的鉴定。

  摘要：

  纯化的禽类3-羟基-3-甲基戊二酰辅酶A裂解酶的催化作用主要取决于该酶的还原状态，其中空气氧化酶的最佳活性不足1％。该酶被巯基定向试剂不可逆地灭活，这种失活的速率高度依赖于关键半胱氨酸的氧化还原状态。用1 mM 4-甲基硝基苯磺酸盐还原的禽裂解酶进行甲基化可导致该酶迅速失活，其ak（inact）值为0.178 min-1。氧化的酶以六倍慢的速度失活（k（inact）= 0.028 min-1）。用反应性底物类似物2-丁酰基-CoA灭活酶显示出对酶氧化还原状态的相似依赖性，在氧化和还原形式下观察到的k（无效）值相差七倍。还原的酶与化学计量的双功能试剂1,3-二溴-2-丙酮（DBP）或N，N'-邻苯撑二马来酰亚胺（PDM）的化学交联与快速失活相吻合。经双功能试剂处理的酶的十二烷基硫酸钠-聚丙烯酰胺钠凝胶电泳显示出两倍于裂解酶单体分子量的条带，表明已形成亚基间交联。用[1-14C]碘乙酸对天然蛋

  DOI：

  10.1002/pro.5560010908
• 作为产物：
  描述：

  3-Hydroxy-3-methylpentanedioate 、 succinyl-CoA(5-) 生成 (S)-Hmg-CoA 、 琥珀酸根
  参考文献：
  名称：

  C7orf10 编码琥珀酸-羟甲基戊二酸辅酶 A 转移酶，该酶将戊二酸转化为戊二酰辅酶 A。

  摘要：

  戊二酸是色氨酸和赖氨酸代谢的副产物，通过使用琥珀酰辅酶 A 作为辅酶供体的转移酶转化为戊二酰辅酶 A 进行代谢。尚未正式鉴定催化这种转化的酶。然而，良性形式的戊二酸尿症（III 型戊二酸尿症）是由于 C7orf10（辅酶 A 转移酶 III 类家族的推定成员）中的突变所致。在目前的工作中，我们表明重组人 C7orf10 催化丁二酰辅酶 A 依赖的戊二酸转化为戊二酰辅酶 A。C7orf10 可以使用许多二羧酸作为 CoA 受体，最好的是戊二酸、琥珀酸、己二酸和 3-羟甲基戊二酸。用 C7orf10-GFP 融合蛋白转染的 CHO 细胞的共聚焦显微镜分析表明 C7orf10 是一种线粒体蛋白，与在其 N 端存在预测的线粒体前肽一致。还研究了在几名 III 型戊二酸尿症患者的纯合状态中发现的错义突变 (p.Arg336Trp) 的影响，该突变在普通人群中以低频率存在。p.Arg336Trp 突变导致在大肠杆菌和

  DOI：

  10.1007/s10545-013-9632-0

文献信息

• <i>Enterococcus faecalis</i> Acetoacetyl-Coenzyme A Thiolase/3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase, a Dual-Function Protein of Isopentenyl Diphosphate Biosynthesis
  作者：Matija Hedl、Autumn Sutherlin、E. Imogen Wilding、Marie Mazzulla、Damien McDevitt、Pamela Lane、John W. Burgner、Kevin R. Lehnbeuter、Cynthia V. Stauffacher、Michael N. Gwynn、Victor W. Rodwell

  DOI：10.1128/jb.184.8.2116-2122.2002

  日期：2002.4.15

  Many bacteria employ the nonmevalonate pathway for synthesis of isopentenyl diphosphate, the monomer unit for isoprenoid biosynthesis. However, gram-positive cocci exclusively use the mevalonate pathway, which is essential for their growth (E. I. Wilding et al., J. Bacteriol. 182:4319-4327, 2000). Enzymes of the mevalonate pathway are thus potential targets for drug intervention. Uniquely, the enterococci possess a single open reading frame, mvaE , that appears to encode two enzymes of the mevalonate pathway, acetoacetyl-coenzyme A thiolase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Western blotting revealed that the mvaE gene product is a single polypeptide in Enterococcus faecalis , Enterococcus faecium , and Enterococcus hirae . The mvaE gene was cloned from E. faecalis and was expressed with an N-terminal His tag in Escherichia coli . The gene product was then purified by nickel affinity chromatography. As predicted, the 86.5-kDa mvaE gene product catalyzed both the acetoacetyl-CoA thiolase and HMG-CoA reductase reactions. Temperature optima, Δ H _a and K _m values, and pH optima were determined for both activities. Kinetic studies of acetoacetyl-CoA thiolase implicated a ping-pong mechanism. CoA acted as an inhibitor competitive with acetyl-CoA. A millimolar K _i for a statin drug confirmed that E. faecalis HMG-CoA reductase is a class II enzyme. The oxidoreductant was NADP(H). A role for an active-site histidine during the first redox step of the HMG-CoA, reductase reaction was suggested by the ability of diethylpyrocarbonate to block formation of mevalonate from HMG-CoA, but not from mevaldehyde. Sequence comparisons with other HMG-CoA reductases suggest that the essential active-site histidine is His756. The mvaE gene product represents the first example of an HMG-CoA reductase fused to another enzyme.

  摘要 许多细菌采用非甲羟戊酸途径合成二磷酸异戊烯酯（异戊烯生物合成的单体）。然而，革兰氏阳性球菌只使用对其生长至关重要的甲羟戊酸途径（E. I. Wilding 等人，《细菌学杂志》182:4319-4327，2000 年）。因此，甲羟戊酸途径的酶是药物干预的潜在目标。与众不同的是，肠球菌拥有一个开放阅读框、 mvaE 似乎编码甲羟戊酸途径的两种酶，即乙酰乙酰辅酶 A 硫醇酶和 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶。Western 印迹显示 mvaE 基因产物是一个单多肽。 粪肠球菌 , 粪肠球菌 和 平肠球菌 .酵母菌 mvaE 基因是从 粪肠球菌 中克隆了 mvaE 基因，并将其 N 端 His 标记在 大肠杆菌 .然后用镍亲和层析法纯化了基因产物。正如预测的那样，86.5 kDa mvaE 基因产物可催化乙酰乙酰-CoA 硫醇酶和 HMG-CoA 还原酶反应。最适温度 Δ H a 和 K m 值和最适 pH 值。乙酰乙酰-CoA 硫醇酶的动力学研究显示了一种乒乓机制。CoA 是一种与乙酰-CoA 竞争的抑制剂。毫摩尔 K i 证实了 粪肠球菌 HMG-CoA 还原酶是一种 II 类酶。氧化还原剂是 NADP（H）。在 HMG-CoA 还原酶反应的第一个氧化还原步骤中，活性位组氨酸起了作用，这是因为二乙基吡咯碳酸酯能够阻止 HMG-CoA 生成甲羟戊酸，但不能阻止甲羟戊酸生成甲醛。与其他 HMG-CoA 还原酶的序列比较表明，重要的活性位点组氨酸是 His756。mvaE mvaE 基因产物是 HMG-CoA 还原酶与另一种酶融合的第一个实例。
• Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin
  作者：G.A. Holdgate、W.H.J. Ward、F. McTaggart

  DOI：10.1042/bst0310528

  日期：2003.6.1

  The statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (HMG-CoAR), and are utilized to decrease levels of atherogenic lipoproteins in patients with, or who are at high risk of, cardiovascular disease. This study describes the inhibition of a recombinant, catalytic fragment of human HMG-CoAR by a new statin, rosuvastatin (CRESTOR®). Binding is reversible and involves an initial complex [inhibition constant involving the enzyme–inhibitor complex (E.I), Ki, ≈1 nM], which undergoes a slow transition (t1/2 to reach steady state is 33–360 s) to give tighter association [steady-state inhibition constant involving E.I and the second E.I complex in a two-step mechanism (E.I*), Ki*, ≈0.1 nM]. At steady state, rosuvastatin is at least as potent as atorvastatin, cerivastatin and simvastatin. It is more potent than fluvastatin and pravastatin. For rosuvastatin, inhibition kinetics are competitive with respect to HMG-CoA and non-competitive when NADPH is varied. At 37°C, binding is linked to a large favourable enthalpy change [ ΔH° =−69.0 kJ/mol (−16.5 kcal/mol)] and a small entropic penalty [T ΔS°=−9.6 kJ/mol (−2.3 kcal/mol)]. These characteristics, and the high affinity relative to that of 3S-HMG-CoA (Kd≈6.6 μM), are discussed in relation to the crystal structures of complexes with HMG-CoAR.

  他汀类药物是3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（HMG-CoAR）的抑制剂，用于降低患有或高风险心血管疾病的患者的动脉粥样硬化脂蛋白水平。本研究描述了一种新的他汀类药物罗伊司他汀（CRESTOR®）对人源HMG-CoAR的重组催化片段的抑制。结合是可逆的，并涉及一个初始复合物[涉及酶-抑制剂复合物（E.I）的抑制常数（Ki）约为1纳摩尔]，该复合物经过缓慢的转化（达到稳态的t1/2为33-360秒），以提供更紧密的关联[涉及E.I和第二个E.I复合物的稳态抑制常数的两步机制（E.I*），Ki*约为0.1纳摩尔]。在稳态下，罗伊司他汀至少与阿托伐他汀、西立伐他汀和辛伐他汀一样有效。它比氟伐他汀和普伐他汀更有效。对于罗伊司他汀，抑制动力学与HMG-CoA相关，而在变化NADPH时则是非竞争性的。在37℃下，结合与大有利焓变化[ΔH°=-69.0千焦/摩尔（-16.5千卡/摩尔）]和小熵惩罚[TΔS°=-9.6千焦/摩尔（-2.3千卡/摩尔）]相关。这些特征和与3S-HMG-CoA（Kd约为6.6微米）相对较高的亲和力与HMG-CoAR的晶体结构有关。
• 3-Hydroxy-3-methylglutaryl-coenzyme A reductase from Haloferax volcanii: purification, characterization, and expression in Escherichia coli
  作者：K M Bischoff、V W Rodwell

  DOI：10.1128/jb.178.1.19-23.1996

  日期：1996.1

  Prior work from this laboratory characterized eukaryotic (hamster) and eubacterial (Pseudomonas mevalonii) 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductases. We report here the characterization of an HMG-CoA reductase from the third domain, the archaea. HMG-CoA reductase of the halobacterium Haloferax volcanii was initially partially purified from extracts of H. volcanii. Subsequently, a portion of the H. volcanii lovastatin (formerly called mevinolin) resistance marker mev was subcloned into the Escherichia coli expression vector pT7-7. While no HMG-CoA reductase activity was detectable following expression in E. coli, activity could be recovered after extracts were exposed to 3 M KCl. Following purification to electrophoretic homogeneity, the specific activity of the expressed enzyme, 24 microU/mg, equaled that of homogeneous hamster or P. mevalonii HMG-CoA reductase. Activity was optimal at pH 7.3. Kms were 66 microM (NADPH) and 60 microM [(S)-HMG-CoA]. (R)-HMG-CoA and lovastatin inhibited competitively with (S)-HMG-CoA. H. volcanii HMG-CoA reductase also catalyzed the reduction of mevaldehyde [optimal activity at pH 6.0; Vmax 11 microU/mg; Kms 32 microM (NADPH), 550 microM [(R,S)-mevaldehyde]] and the oxidative acylation of mevaldehyde [optimal activity at pH 8.0; Vmax 2.1 microU/mg; Kms 350 microM (NADP+), 300 microM (CoA), 470 microM [(R,S)-mevaldehyde]]. These properties are comparable to those of hamster and P. mevalonii HMG-CoA reductases, suggesting a similar catalytic mechanism.

  该实验室之前的工作表征了真核生物（仓鼠）和真细菌（甲烷假单胞菌）3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶。我们在这里报道了来自第三域——古菌的HMG-CoA还原酶的特性。首先从H. volcanii提取物中部分纯化了卤菌Haloferax volcanii的HMG-CoA还原酶。随后，将H. volcanii的洛伐他汀（曾称为梅维诺林）抗性标记mev的一部分亚克隆到大肠杆菌表达载体pT7-7中。在大肠杆菌中表达后未检测到HMG-CoA还原酶活性，但在提取物暴露于3 M KCl后可以恢复活性。在纯化到电泳同质性后，表达酶的比活性为24微米单位/毫克，与同质的仓鼠或P. mevalonii HMG-CoA还原酶相等。酶活性在pH 7.3时最佳。Km值为66微米（NADPH）和60微米[(S)-HMG-CoA]。[（R）-HMG-CoA]和洛伐他汀与[(S)-HMG-CoA]竞争性抑制。H. volcanii HMG-CoA还原酶还催化了甲醛的还原[在pH 6.0时最佳活性；Vmax为11微米单位/毫克；Km值为32微米（NADPH），550微米[(R,S)-甲醛]]和甲醛的氧化酰化[在pH 8.0时最佳活性；Vmax为2.1微米单位/毫克；Km值为350微米（NADP+），300微米（CoA），470微米[(R,S)-甲醛]]。这些特性与仓鼠和P. mevalonii HMG-CoA还原酶的特性相当，表明具有相似的催化机制。
• <i>Enterococcus faecalis</i> 3-Hydroxy-3-Methylglutaryl Coenzyme A Synthase, an Enzyme of Isopentenyl Diphosphate Biosynthesis
  作者：Autumn Sutherlin、Matija Hedl、Barbara Sanchez-Neri、John W. Burgner、Cynthia V. Stauffacher、Victor W. Rodwell

  DOI：10.1128/jb.184.15.4065-4070.2002

  日期：2002.8

  inhibitors for use as antibiotics. We used the PCR and Enterococcus faecalis genomic DNA to isolate the mvaS gene that encodes 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, the second enzyme of the mevalonate pathway. mvaS was expressed in Escherichia coli from a pET28 vector with an attached N-terminal histidine tag. The expressed enzyme was purified by affinity chromatography on Ni(2+)-agarose

  异戊二烯前体异戊烯基二磷酸酯（IPP）的生物合成通过两个不同的途径进行。序列比较和微生物学数据表明，革兰氏阳性球菌的多药耐药菌株仅利用甲羟戊酸途径进行IPP生物合成。因此，细菌甲羟戊酸途径酶为开发用作抗生素的活性定点抑制剂提供了潜在的靶标。我们使用PCR和粪肠球菌基因组DNA分离了编码3-羟-3-甲基戊二酰辅酶A（HMG-CoA）合酶（甲羟戊酸途径的第二种酶）的mvaS基因。mvaS在大肠杆菌中由带有附着的N端组氨酸标签的pET28载体表达。通过在Ni（2 +）-琼脂糖上进行亲和色谱纯化表达的酶，使其具有明显的均一性和10μmol/ min / mg的比活性。分析超离心表明该酶是二聚体（质量，83.9 kDa； s（20，w），5.3）。最佳活性发生在2.0 mM MgCl（2）中，温度为37（o）C。DeltaH（a）为6,000卡路里。pH活性曲线（在pH值为9.8时具有最佳活性）对于
• Active Form ofPseudomonas mevalonii3-Hydroxy-3-methylglutaryl Coenzyme A Reductase
  作者：Kenneth S. Rogers、Victor W. Rodwell、Paul Geiger

  DOI：10.1006/bmme.1997.2596

  日期：1997.6

  radius of 59.7 A for Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.88) and its His381Asn, His381Gln, and His381Lys mutant enzymes. Comparison of this Stokes radius with the radius calculated from the crystal structure indicated that the active form of P. mevalonii HMG-CoA reductase was a hexamer and not a dimer as previously thought. The Stokes radius

  基于多次凝胶渗透色谱实验，我们报道了美黑假单胞菌3-羟-3-甲基戊二酰辅酶A还原酶（HMG-CoA还原酶； EC 1.1.1.88）及其His381Asn，His381Gln和His381Lys突变酶的斯托克斯半径为59.7A。 。将该斯托克斯半径与从晶体结构计算出的半径进行比较表明，P。mevalonii HMG-CoA还原酶的活性形式是六聚体，而不是先前认为的二聚体。在Svedberg方程中使用Stokes半径，S26，w为11.0和估计的V为0.723来计算水杨假单胞菌HMG-CoA还原酶的无水分子量为270,084 Da（单体质量为45,538 Da），与酶是溶液中的六聚体。检查的所有标准蛋白质的斯托克斯半径与其分配系数Kd的反误差函数互补相关。Kd与标准蛋白质分子量的对数不相关。八个非标准蛋白质的斯托克斯半径与最长轴的结晶半径相匹配。这表明，其晶体形式的蛋白质的冷冻构象可以决定其在溶液中的形状。