Molecular enzymology of 5-aminolevulinate synthase, the gatekeeper of heme biosynthesis.
Molecular enzymology of 5-aminolevulinate synthase, the gatekeeper of heme biosynthesis.
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DOI：
10.1016/j.bbapap.2010.12.015
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发表时间：
2011-11
影响因子：
3.2
通讯作者：
Ferreira, Gloria C.
中科院分区：
文献类型：
--
作者：
Hunter, Gregory A.;Ferreira, Gloria C.
吡哆醛-5 '-磷酸（PLP）是同二聚体线粒体酶5-氨基乙酰丙酸合酶（ALAS）的必需辅因子，其控制动物、真菌和变形菌α亚类中进入卟啉生物合成途径的代谢通量。最近的工作提供了一个解释，这种酶可以利用PLP催化机制不寻常的切割不是一个，而是两个底物氨基酸α-碳键，而不违反PLP反应类型特异性的立体电子控制理论。具有讽刺意味的是，复杂的化学反应在动力学上并不重要，而是活性位点环的运动定义了kcat，并最终定义了卟啉生物合成的速率。酶的动力学行为与平衡有序诱导配合机制一致，其中甘氨酸必须首先结合，然后利用与琥珀酰辅酶A的一部分固有结合能来扰乱酶构象平衡，使其朝向发生催化的闭合状态。回复到开放构象，与ALA解离一致，是反应循环中最慢的步骤。各种各样的环突变已与多动症相关，表明酶已进化为有目的地缓慢，可能作为一种手段，以允许响应于尚未发现的变构型效应物而快速上调活性。最近发现，人类红系ALAS突变可能与两种非常不同的疾病相关。下调活性的突变可导致X连锁铁粒幼细胞性贫血，其特征在于线粒体中异常高的铁水平，而上调活性的突变与X连锁显性原卟啉症相关，相反，其通过异常高的卟啉水平进行表型鉴定。这篇文章是特刊的一部分，题为：磷酸吡哆醛酶学。
Pyridoxal-5'-phosphate (PLP) is an obligatory cofactor for the homodimeric mitochondrial enzyme 5-aminolevulinate synthase (ALAS), which controls metabolic flux into the porphyrin biosynthetic pathway in animals, fungi, and the α-subclass of proteobacteria. Recent work has provided an explanation for how this enzyme can utilize PLP to catalyze the mechanistically unusual cleavage of not one but two substrate amino acid α-carbon bonds, without violating the theory of stereoelectronic control of PLP reaction-type specificity. Ironically, the complex chemistry is kinetically insignificant, and it is the movement of an active site loop that defines kcat and ultimately, the rate of porphyrin biosynthesis. The kinetic behavior of the enzyme is consistent with an equilibrium ordered induced-fit mechanism wherein glycine must bind first and a portion of the intrinsic binding energy with succinyl-Coenzyme A is then utilized to perturb the enzyme conformational equilibrium towards a closed state wherein catalysis occurs. Return to the open conformation, coincident with ALA dissociation, is the slowest step of the reaction cycle. A diverse variety of loop mutations have been associated with hyperactivity, suggesting the enzyme has evolved to be purposefully slow, perhaps as a means to allow for rapid up-regulation of activity in response to an as yet undiscovered allosteric type effector. Recently it was discovered that human erythroid ALAS mutations can be associated with two very different diseases. Mutations that down-regulate activity can lead to X-linked sideroblastic anemia, which is characterized by abnormally high iron levels in mitochondria, while mutations that up-regulate activity are associated with X-linked dominant protoporphyria, which in contrast is phenotypically identified by abnormally high porphyrin levels. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology.
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影响因子：
11.4
作者：
Astner, I;Schulze, JO;Heinz, DW
通讯作者：
Heinz, DW
影响因子：
64.8
作者：
Eisenmesser, EZ;Millet, O;Kern, D
通讯作者：
Kern, D
DOI：
10.1098/rstb.1976.0005
发表时间：
1976-01-01
期刊：
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AKHTAR, M;ABBOUD, MM;ZAMAN, Z
通讯作者：
ZAMAN, Z
影响因子：
4.4
作者：
Gollnick SO;Brackett CM
通讯作者：
Brackett CM
影响因子：
--
作者：
Hwang JJ;Ghobrial IM;Anderson KC
通讯作者：
Anderson KC