Unexpected inhibition of S-adenosyl-l-homocysteine hydrolase by a guanosine nucleoside

Seley, Katherine L.; Quirk, Stephen; Salim, Samer; Zhang, Liang; Hagos, Asmerom

doi:10.1016/s0960-894x(03)00331-7

Cited by 39 publications

(41 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It quickly became apparent however, that the molecule could be useful as an enzyme active site probe (35). The inherent flexibility of the structurally unique nucleoside analogue permits the pyrimidine ring to rotate about the imidazole ring via the extra carbon-carbon bond.…”

Section: Discussionmentioning

confidence: 99%

Identification of Catalytic Amino Acids in the Human GTP Fucose Pyrophosphorylase Active Site

Quirk

Seley

2005

Biochemistry

Self Cite

View full text Add to dashboard Cite

GTP-l-fucose pyrophosphorylase(GFPP) catalyzes the reversible formation of the nucleotide-sugar GDP-beta-l-fucose from guanosine triphosphate and beta-l-fucose-1-phosphate. The enzyme functions primarily in the mammalian liver and kidney to salvage free fucose during the breakdown of glycoproteins and glycolipids. GFPP shares little primary sequence identity with other nucleotide-sugar metabolizing enzymes, and the three-dimensional structure of the protein is unknown. The enzyme does contain several sequences that could be nucleotide binding sites, but none of them are an exact match to consensus sequences. Using a combination of site-directed mutagenesis and UV photoaffinity cross-linking, we have identified five amino acid residues that are critical for catalysis. Some of these amino acids are found within the poorly conserved nucleotide binding consensus structures, while others represent new motifs. Two active site lysines can be cross-linked to photoaffinity probes. The site of cross-linking depends on the probe used. The identification of these critical residues highlights how distinct GFPP is from other nucleotide-sugar pyrophosphorylases.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of Catalytic Amino Acids in the Human GTP Fucose Pyrophosphorylase Active Site

Quirk

Seley

2005

Biochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…In that regard, we have previously reported that a flexible guanosine nucleoside ( 1 , Figure 1), served as an inhibitor of S-adenosylhomocysteine hydrolase (SAHase), an adenosine-metabolizing enzyme. [10] The flexibility of the base unit yielded rotational and conformational changes that allowed the guanosine analogue (Flex-G) to mimic adenosine. [10] In addition to this, our investigations with GTP fucose pyrophosphorylase (GFPP) have shown that the triphosphate of Flex-G (Flex-GTP, 2 ) was preferred over the natural substrate, guanosine triphosphate (GTP).…”

Section: Introductionmentioning

confidence: 99%

“…[10] The flexibility of the base unit yielded rotational and conformational changes that allowed the guanosine analogue (Flex-G) to mimic adenosine. [10] In addition to this, our investigations with GTP fucose pyrophosphorylase (GFPP) have shown that the triphosphate of Flex-G (Flex-GTP, 2 ) was preferred over the natural substrate, guanosine triphosphate (GTP). [11] The ability of Flex-GTP to interact with secondary amino acids within the binding site led to more favorable binding interactions, thereby increasing the affinity in GFPP when compared to GTP.…”

Section: Introductionmentioning

confidence: 99%

“Reverse” Carbocyclic Fleximers: Synthesis of a New Class of Adenosine Deaminase Inhibitors

Zimmermann¹,

Sadler²,

O’Daniel³

et al. 2013

Nucleosides, Nucleotides and Nucleic Acids

View full text Add to dashboard Cite

A series of flexible carbocyclic pyrimidine nucleosides has been designed and synthesized. In contrast to previously reported “fleximers” from our laboratory, these analogues have the connectivity of the heterocyclic base system “reversed”, where the pyrimidine ring is attached to the sugar moiety, rather than the five membered imidazole ring. As was previously seen with the ribose fleximers, their inherent flexibility should allow them to adjust to enzyme binding site mutations, as well as increase the affinity for atypical enzymes. Preliminary biological screening has revealed surprising inhibition of adenosine deaminase, despite their lack of resemblance to adenosine.

show abstract

“…4 The flexibility of the nucleobase allowed the purine components to rotate and reposition to allow Flex-G to mimic adenosine. 4,5 In addition to SAHase inhibition, it was also found that the triphosphate analogue of Flex-G was a significantly better substrate for GTP fucose pyrophosphorylase (GFPP) than the natural substrate GTP, and was able to retain full activity when key amino acid residues required for GTP recognition were mutated. 6,7 Notably, GTP was rendered completely inactive.…”

Section: Introductionmentioning

confidence: 99%

Carbocyclic 5′-nor “reverse” fleximers. Design, synthesis, and preliminary biological activity

et al. 2011

View full text Add to dashboard Cite

A series of 5′-nor carbocyclic “reverse” flexible nucleosides or “fleximers” have been designed wherein the nucleobase scaffold resembles a “split” purine as well as a substituted pyrimidine. This modification was employed to explore recognition by both purine and pyrimidine metabolizing enzymes. The synthesis of the carbocyclic fleximers and the results of their preliminary biological screening are described herein.

show abstract

Unexpected inhibition of S-adenosyl-l-homocysteine hydrolase by a guanosine nucleoside

Cited by 39 publications

References 9 publications

Identification of Catalytic Amino Acids in the Human GTP Fucose Pyrophosphorylase Active Site

Identification of Catalytic Amino Acids in the Human GTP Fucose Pyrophosphorylase Active Site

“Reverse” Carbocyclic Fleximers: Synthesis of a New Class of Adenosine Deaminase Inhibitors

Carbocyclic 5′-nor “reverse” fleximers. Design, synthesis, and preliminary biological activity

Contact Info

Product

Resources

About