Structure of an antitumor antibiotic, spergualin.

Umezawa, Hamao; Kondo, Shinichi; Iinuma, Hisae; Kunimoto, Setsuko; Ikeda, Yoko; Iwasawa, Hiroyuki; Ikeda, Daishiro; Takeuchi, Tomio

doi:10.7164/antibiotics.34.1622

Cited by 118 publications

(45 citation statements)

References 3 publications

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“…The natural product analog, 15-deoxyspergualin, is an agonist of Hsp70 that binds outside the nucleotide-binding site (63)(64)(65). Recent work by Brodsky and co-workers (66,67) has shown that certain synthetically accessible dihydropyrimidines, which structurally mimic 15-deoxyspergualin, can likewise enhance ATPase activity and regulate protein translocation.…”

Section: Resultsmentioning

confidence: 99%

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Evans

Wisén

Gestwicki

2006

Journal of Biological Chemistry

344

304

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Alzheimer disease is a neurological disorder that is characterized by the presence of fibrils and oligomers composed of the amyloid ␤ (A␤) peptide. In models of Alzheimer disease, overexpression of molecular chaperones, specifically heat shock protein 70 (Hsp70), suppresses phenotypes related to A␤ aggregation. These observations led to the hypothesis that chaperones might interact with A␤ and block self-association. However, although biochemical evidence to support this model has been collected in other neurodegenerative systems, the interaction between chaperones and A␤ has not been similarly explored. Here, we examine the effects of Hsp70/40 and Hsp90 on A␤ aggregation in vitro. We found that recombinant Hsp70/40 and Hsp90 block A␤ self-assembly and that these chaperones are effective at substoichiometric concentrations (ϳ1:50). The antiaggregation activity of Hsp70 can be inhibited by a nonhydrolyzable nucleotide analog and encouraged by pharmacological stimulation of its ATPase activity. Finally, we were interested in discerning what type of amyloid structures can be acted upon by these chaperones. To address this question, we added Hsp70/40 and Hsp90 to pre-formed oligomers and fibrils. Based on thioflavin T reactivity, the combination of Hsp70/40 and Hsp90 caused structural changes in oligomers but had little effect on fibrils. These results suggest that if these chaperones are present in the same cellular compartment in which A␤ is produced, Hsp70/40 and Hsp90 may suppress the early stages of self-assembly. Thus, these results are consistent with a model in which pharmacological activation of chaperones might have a favorable therapeutic effect on Alzheimer disease.The amyloid diseases are a collection of protein misfolding disorders associated with the formation of distinctive fibrils (reviewed in Refs. 1-5). Alzheimer disease is one of the most common amyloid diseases, and it is characterized by fibrils composed of A␤, 2 a 39 -43-amino acid proteolytic fragment of the amyloid precursor protein (reviewed in Ref. 6). Upon release from amyloid precursor protein, A␤ becomes enriched in ␤-sheet structure and acquires the propensity to self-assemble (7). Initial theories to explain the pathology of AD focused on the involvement of the visually striking fibrils, but more recent evidence has strongly supported a role for soluble oligomers (reviewed in Refs. 3 and 8 -10). A␤ oligomers can be prepared in vitro (11,12), biosynthesized by cultured cells (13,14), or collected from AD tissues (15), and in all cases, these structures are highly neurotoxic. Despite these important observations, numerous questions about the basis of disease are unanswered. For example, although there is active research in this area (8,11,16), the number of A␤ monomers present in an oligomer has not been fully described. Moreover, the subcellular site(s) of oligomer production and the conditions that lead to their assembly are still debated; fibrils are found in extracellular space, but there is growing evidence that oligomers may be pr...

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Section: Resultsmentioning

confidence: 99%

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Evans

Wisén

Gestwicki

2006

Journal of Biological Chemistry

344

304

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“…Although hemiaminals are in general not stable under aqueous conditions, a few carbinolamide-bearing natural products have been identified, such as the echinocandin type anti-fungal antibiotics anidulafungin (known as Eraxis) (23) and micafungin (known as Mycamine) (24), spergualin (25), zampanolide (26), bicyclomycin (Bicozamycin) (27)(28)(29), epolactaene (30), and oteromycin (31) (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of tlmK Unveiling Unstable Carbinolamide Intermediates in the Tallysomycin Biosynthetic Pathway

Wang

Tao

Wendt-Pienkoski

et al. 2009

Journal of Biological Chemistry

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Tallysomycins (TLMs) belong to the bleomycin family of anticancer antibiotics. TLMs differ from bleomycins primarily by the presence of a 4-amino-4,6-dideoxy-L-talose sugar attached to C-41 as part of a glycosylcarbinolamide. We previously proposed, on the basis of bioinformatics analysis of the tlm biosynthetic gene cluster from Streptoalloteichus hindustanus E465-94 ATCC 31158, that the tlmK gene is responsible for the attachment of this sugar moiety. We now report that inactivation of tlmK in S. hindustanus abolished TLM A and TLM B production, the resultant ⌬tlmK mutant instead accumulated five new metabolites, and introduction of a functional copy of tlmK to the ⌬tlmK mutant restored TLM A and TLM B production. Two major metabolites, TLM K-1 and TLM K-2, together with three minor metabolites, TLM K-3, TLM K-4, and TLM K-5, were isolated from the ⌬tlmK mutant, and their structures were elucidated. These findings provide experimental evidence supporting the previous functional assignment of tlmK to encode a glycosyltransferase and unveil two carbinolamide pseudoaglycones as key intermediates in the TLM biosynthetic pathway. TlmK stabilizes the carbinolamide intermediates by glycosylating their hemiaminal hydroxyl groups, thereby protecting them from hydrolysis during TLM biosynthesis. In the absence of TlmK, the carbinolamide intermediates fragment to produce an amide TLM K-1 and aldehyde intermediates, which undergo further oxidative fragmentation to afford carboxylic acids TLM K-2, TLM K-3, TLM K-4, and TLM K-5. Tallysomycins (TLMs)3 belong to the bleomycin (BLM) family of glycopeptide antitumor antibiotics (1, 2) (Fig. 1). The BLMs are currently used clinically under the trade name Blenoxane in combination with a number of other agents for the treatment of Hodgkin lymphoma, carcinomas of the skin, head, and neck, and testicular cancers. Early development of drug resistance and dose-dependent pulmonary toxicity are major limitations of BLMs in chemotherapy (3, 4). Structural modifications to this family of natural products are necessary for improvement in efficacy and reduction of toxicity. Although numerous BLM analogs have been synthesized (5, 6), total synthesis remains of limited practical value because of the complex scaffold of this entire family of natural products. Recent cloning and characterization of the BLM, TLM, and zorbamycin biosynthetic gene clusters from Streptomyces verticillus ATCC15003 (7), Streptoalloteichus hindustanus E465-94 (ATCC 31158) (8), and Streptomyces flavoviridis ATCC21892 (9) opened the possibility toward the production of novel BLM analogs via genetic metabolic engineering approaches.TLMs are structurally related to BLMs but differ from BLMs in three ways; (i) the presence of two hydroxyl groups within the aminoethylbithiazole moiety, one of which is conjugated to a 4-amino-4,6-dideoxy-L-talose sugar as part of a glycosylcarbinolamide, (ii) the presence of two series of C-terminal amine moieties with (A series) or without (B series) a ␤-lysine moiety in the subterminal pos...

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“…Spergualin showed a marked inhibition against experimental mouse tumors, and the structure was determined to be (-)-(I 5S)-1-amino-l9-guanidino-11,15-dihydroxy-4, 9,12-triazanonadecane-10,13-dione2>. In thiscommunication, we report the synthesis of epimeric spergualin (1) and epimeric (15R)-spergualin (2), and separation of 1 into natural (-)-spergualin (la) and unnatural (+)-spergualin (1b). * The total synthesis of 1 has been accomplished by acid-catalyzed condensation of (S)-7-guanidino-3-hydroxyheptanamide (3) and 11-amino-l,1-dihydroxy-3,8-diazaundecan-2-one (4, a hydrate of glyoxylylspermidine).…”

Section: The Total Synthesis Of Spergualin An Antitumor Antibioticmentioning

confidence: 92%

The total synthesis of spergualin, an antitumor antibiotic.

et al. 1981

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Structure of an antitumor antibiotic, spergualin.

Cited by 118 publications

References 3 publications

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid β-(1–42) Aggregation in Vitro

Functional Characterization of tlmK Unveiling Unstable Carbinolamide Intermediates in the Tallysomycin Biosynthetic Pathway

The total synthesis of spergualin, an antitumor antibiotic.

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