Crystal Structure of S-Adenosyl-l-Homocysteine Hydrolase from the Human Malaria Parasite Plasmodium falciparum

Tanaka, Nobutada; Nakanishi, Mahito; Kusakabe, Yoshio; Shiraiwa, K.; Yabe, Saori; Ito, Yosoji; Kitade, Yukio; Nakamura, Kazuo

doi:10.1016/j.jmb.2004.08.104

Cited by 60 publications

(83 citation statements)

References 25 publications

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“…ARI strongly inhibits the Mtb SAHH enzyme, with an IC 50 of 0.2 mM (see Table 1). This is commensurate with inhibition activity reported for ARI against SAHH from other organisms (1.1 mM vs. Homo sapiens, 3.1 mM vs. P. falciparum) (Tanaka et al 2004). The strong inhibitory activity of ARI can be explained based on the mechanism.…”

Section: Complexes Of Sahh With Nad + and Inhibitorssupporting

confidence: 88%

“…4) that packs on the surface of domain I, before rejoining helix a11. The insertion is similar to that observed in the P. falciparum structure (PDB ID: 1V8B) (Tanaka et al 2004). However, in 1V8B, helix a10 is extended by one additional turn before the strand begins, so they do not perfectly superimpose (Fig.…”

Section: Overall Structuresupporting

confidence: 79%

“…Thus, the fluorine atom, which is the only chemical difference, has a significant effect on binding affinity. A similar IC 50 for 2FA has been observed for the human SAHH homolog (63 mM) (Tanaka et al 2004). However, in P. falciparum, polar substitutions at the 2-position have been found to have increased relative inhibition, which was attributed to the replacement of Thr60 (human) by Cys59, creating additional space in the ADO-binding pocket (Tanaka et al 2004).…”

Section: Complexes Of Sahh With Nad + and Inhibitorssupporting

confidence: 72%

“…A similar IC 50 for 2FA has been observed for the human SAHH homolog (63 mM) (Tanaka et al 2004). However, in P. falciparum, polar substitutions at the 2-position have been found to have increased relative inhibition, which was attributed to the replacement of Thr60 (human) by Cys59, creating additional space in the ADO-binding pocket (Tanaka et al 2004). Importantly, however, in contrast to ARI, 2FA was found to have bacteriocidal activity against Mycobacterium smegmatis in a whole-cell assay (MIC of 32 mM, whereas ARI and DZA had MICs >100 mM, Table 1).…”

Section: Complexes Of Sahh With Nad + and Inhibitorssupporting

confidence: 72%

“…The crystal structure for SAHH has been solved for three different organisms to date, all eukaryotic: human, rat (Rattus rattus), and malaria (Plasmodium falciparum) (Turner et al 1998;Hu et al 1999;Komoto et al 2000;Huang et al 2002;Takata et al 2002;Yang et al 2003;Tanaka et al 2004;Yamada et al 2005Yamada et al , 2007. The proposed SAHH catalytic mechanism involves a sequence of steps as follows (Fig.…”

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confidence: 99%

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Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

et al. 2008

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S-adenosylhomocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a central role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine (SAH) and S-adenosylmethionine. We report the first prokaryotic crystal structure of SAHH, from Mycobacterium tuberculosis (Mtb), in complex with adenosine (ADO) and nicotinamide adenine dinucleotide. Structures of complexes with three inhibitors are also reported: 39-keto aristeromycin (ARI), 2-fluoroadenosine, and 3-deazaadenosine. The ARI complex is the first reported structure of SAHH complexed with this inhibitor, and confirms the oxidation of the 39 hydroxyl to a planar keto group, consistent with its prediction as a mechanism-based inhibitor. We demonstrate the in vivo enzyme inhibition activity of the three inhibitors and also show that 2-fluoradenosine has bactericidal activity. While most of the residues lining the ADO-binding pocket are identical between Mtb and human SAHH, less is known about the binding mode of the homocysteine (HCY) appendage of the full substrate. We report the 2.0 Å resolution structure of the complex of SAHH cocrystallized with SAH. The most striking change in the structure is that binding of HCY forces a rotation of His363 around the backbone to flip out of contact with the 59 hydroxyl of the ADO and opens access to a nearby channel that leads to the surface. This complex suggests that His363 acts as a switch that opens up to permit binding of substrate, then closes down after release of the cleaved HCY. Differences in the entrance to this access channel between human and Mtb SAHH are identified.

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Section: Complexes Of Sahh With Nad + and Inhibitorssupporting

confidence: 88%

Section: Overall Structuresupporting

confidence: 79%

Section: Complexes Of Sahh With Nad + and Inhibitorssupporting

confidence: 72%

Section: Complexes Of Sahh With Nad + and Inhibitorssupporting

confidence: 72%

mentioning

confidence: 99%

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Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

et al. 2008

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S‐Adenosyl‐l‐Methionine Salvage Impacts Psilocybin Formation in “Magic” Mushrooms

et al. 2020

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Quinolone Analogs 14: Synthesis of Antimalarial 1‐Aryl‐3‐(4‐quinolon‐2‐yl)ureas and Related Compounds

Kurasawa

Yoshida

Yamazaki

et al. 2014

Journal of Heterocyclic Chem

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The 4‐quinolone‐2‐carbohydrazide 6a was converted into 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a, 5b, 5c, 5d, 5e, 1‐aryl‐3‐(4‐quinolon‐2‐yl)imidazolidine‐2,4‐diones 9a,9b, and N‐(4‐quinolon‐2‐yl)carbamates 10a,10b via 4‐quinolone‐2‐carbonylazide 7a. The 4‐methoxyquinoline‐2‐carbohydrazide 6b was also transformed into 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)ureas 11a, 11b, 11c, 11d, 1‐aryl‐3‐(4‐methoxyquinolin‐2‐yl)imidazolidine‐2,4‐diones 12a,12b, and N‐(4‐methoxyquinolin‐2‐yl)carbamates 13a,13b via 4‐methoxyquinoline‐2‐carbonylazide 7b. Some of the 1‐aryl‐3‐(4‐quinolon‐2‐yl)ureas 5a, 5b, 5c, 5d, 5e showed the in vitro antimalarial activity to chloroquine‐resistant Plasmodium falciparum, wherein IC50 was 0.93 to 4.00 μM.

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Crystal Structure of S-Adenosyl-l-Homocysteine Hydrolase from the Human Malaria Parasite Plasmodium falciparum

Cited by 60 publications

References 25 publications

Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

Crystal structures of Mycobacterium tuberculosis S‐adenosyl‐L‐homocysteine hydrolase in ternary complex with substrate and inhibitors

S‐Adenosyl‐l‐Methionine Salvage Impacts Psilocybin Formation in “Magic” Mushrooms

Quinolone Analogs 14: Synthesis of Antimalarial 1‐Aryl‐3‐(4‐quinolon‐2‐yl)ureas and Related Compounds

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