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Structural studies of methylenetetra...

Pejchal, Robert.

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Structural studies of methylenetetrahydrofolate reductase and cobalamin-independent methionine synthase: Back-to-back enzymes in one-carbon metabolism.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Structural studies of methylenetetrahydrofolate reductase and cobalamin-independent methionine synthase: Back-to-back enzymes in one-carbon metabolism./
Author:	Pejchal, Robert.
Description:	243 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0881.
Contained By:	Dissertation Abstracts International66-02B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3163909
ISBN:	0496985078

Structural studies of methylenetetrahydrofolate reductase and cobalamin-independent methionine synthase: Back-to-back enzymes in one-carbon metabolism.
Pejchal, Robert.

Structural studies of methylenetetrahydrofolate reductase and cobalamin-independent methionine synthase: Back-to-back enzymes in one-carbon metabolism. - 243 p.

Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0881.

Thesis (Ph.D.)--University of Michigan, 2005.

The reduction of methylenetetrahydrofolate (CH2-H4folate) to methyltetrahydrofolate (CH3-H4folate) is the penultimate step in methionine biosynthesis. This reaction is catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR), which uses a flavin cofactor to catalyze hydride transfer from reduced pyridine nucleotide to folate. It is the only enzyme known to catalyze direct chemistry between folate and flavin. The MTHFR reaction is the sole source of CH3-H4folate for use by methionine synthase, which transfers the folate-bound methyl group to homocysteine (Hcy). Two distinct enzymes catalyze this transfer: B 12-dependent methionine synthase (MetH) and B12-independent methionine synthase (MetE).

ISBN: 0496985078Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Structural studies of methylenetetrahydrofolate reductase and cobalamin-independent methionine synthase: Back-to-back enzymes in one-carbon metabolism.
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100 1 $a Pejchal, Robert. $3 1902280
245 1 0 $a Structural studies of methylenetetrahydrofolate reductase and cobalamin-independent methionine synthase: Back-to-back enzymes in one-carbon metabolism.
300 $a 243 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0881.
500 $a Chair: Martha L. Ludwig.
502 $a Thesis (Ph.D.)--University of Michigan, 2005.
520 $a The reduction of methylenetetrahydrofolate (CH2-H4folate) to methyltetrahydrofolate (CH3-H4folate) is the penultimate step in methionine biosynthesis. This reaction is catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR), which uses a flavin cofactor to catalyze hydride transfer from reduced pyridine nucleotide to folate. It is the only enzyme known to catalyze direct chemistry between folate and flavin. The MTHFR reaction is the sole source of CH3-H4folate for use by methionine synthase, which transfers the folate-bound methyl group to homocysteine (Hcy). Two distinct enzymes catalyze this transfer: B 12-dependent methionine synthase (MetH) and B12-independent methionine synthase (MetE).
520 $a MTHFR does not include any established nucleotide-binding sequence motifs. To determine how substrates are bound, I have analyzed the crystal structures of E. coli MTHFR with bound NADH and CH3-H 4folate. These structures complement the previously determined substrate-free form and allow an understanding of how this enzyme is able to accommodate two different substrates using one active site landscape. In contrast to other flavin enzymes, MTHFR adopts a Spartan strategy where only minor side chain rearrangements are used to differentiate between substrates.
520 $a While MetE and MetH are both zinc metalloenzymes, they show no sequence homology and have different cofactor requirements. MetH recruits one of nature's most powerful and rare cofactors while MetE is somehow able to catalyze the same difficult chemistry without it. Given these criteria, to what degree are their structural mechanisms evolutionarily constrained? I have solved the crystal structure of MetE from Thermotoga maritima (TM1286) in substrate-free form and in binary complexes with CH3-H 4folate and Hcy. MetE adopts a unique face-to-face double barrel structure that evolved by gene duplication. Comparison with the recently determined structures of MetH reveals that both enzymes use zinc-adapted (betaalpha) 8 barrels to activate Hcy but display highly dissimilar CH3-H 4folate binding strategies. Interestingly, the unique structural adaptations of MetE are replicated in the enzyme uroporphyrinogen decarboxylase (UroD), which is not a metalloprotein and catalyzes a completely unrelated reaction. These findings support the theory that function recruits form in enzyme evolution.
590 $a School code: 0127.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Biology, General. $3 1018625
690 $a 0487
690 $a 0306
710 2 0 $a University of Michigan. $3 777416
773 0 $t Dissertation Abstracts International $g 66-02B.
790 1 0 $a Ludwig, Martha L., $e advisor
790 $a 0127
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3163909