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Dive into the research topics where Khaled H. Almabruk is active.

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Featured researches published by Khaled H. Almabruk.


eLife | 2015

De novo synthesis of a sunscreen compound in vertebrates

Andrew R. Osborn; Khaled H. Almabruk; Garrett Holzwarth; Shumpei Asamizu; Jane LaDu; Kelsey M. Kean; P. Andrew Karplus; Robert L. Tanguay; Alan T. Bakalinsky; Taifo Mahmud

Ultraviolet-protective compounds, such as mycosporine-like amino acids (MAAs) and related gadusols produced by some bacteria, fungi, algae, and marine invertebrates, are critical for the survival of reef-building corals and other marine organisms exposed to high-solar irradiance. These compounds have also been found in marine fish, where their accumulation is thought to be of dietary or symbiont origin. In this study, we report the unexpected discovery that fish can synthesize gadusol de novo and that the analogous pathways are also present in amphibians, reptiles, and birds. Furthermore, we demonstrate that engineered yeast containing the fish genes can produce and secrete gadusol. The discovery of the gadusol pathway in vertebrates provides a platform for understanding its role in these animals, and the possibility of engineering yeast to efficiently produce a natural sunscreen and antioxidant presents an avenue for its large-scale production for possible use in pharmaceuticals and cosmetics. DOI: http://dx.doi.org/10.7554/eLife.05919.001


Journal of Biological Chemistry | 2014

Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis

Aeshna Nigam; Khaled H. Almabruk; Anjali Saxena; Jongtae Yang; Udita Mukherjee; Hardeep Kaur; Puneet Kohli; Rashmi Kumari; Priya Singh; Lev N. Zakharov; Yogendra Singh; Taifo Mahmud; Rup Lal

Background: The emergence of drug-resistant tuberculosis has called for the discovery of new antitubercular drugs. Results: We successfully generated 24-desmethylrifampicin by modifying the rifamycin polyketide backbone. Conclusion: 24-Desmethylrifamycin showed better antibacterial activity than rifampicin against multidrug-resistant strains of Mycobacterium tuberculosis. Significance: The combined genetic-synthetic strategy used in the study has opened up new avenues for generating more rifamycin analogs. Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy, and AIDS-related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin-resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase domain of module 6 of rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-Desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.


Organic Letters | 2013

Mutasynthesis of fluorinated pactamycin analogues and their antimalarial activity.

Khaled H. Almabruk; Wanli Lu; Yuexin Li; Mostafa Abugreen; Jane X. Kelly; Taifo Mahmud

A mutasynthetic strategy has been used to generate fluorinated TM-025 and TM-026, two biosynthetically engineered pactamycin analogues produced by Streptomyces pactum ATCC 27456. The fluorinated compounds maintain excellent activity and selectivity toward chloroquine-sensitive and multidrug-resistant strains of malarial parasites as the parent compounds. The results also provide insights into the biosynthesis of 3-aminobenzoic acid in S. pactum.


ACS Chemical Biology | 2017

Evolution and Distribution of C7–Cyclitol Synthases in Prokaryotes and Eukaryotes

Andrew R. Osborn; Kelsey M. Kean; Khaled M. Alseud; Khaled H. Almabruk; Shumpei Asamizu; Janet A. Lee; P. Andrew Karplus; Taifo Mahmud

2-Epi-5-epi-valiolone synthase (EEVS), a C7-sugar phosphate cyclase (SPC) homologous to 3-dehydroquinate synthase (DHQS), was discovered during studies of the biosynthesis of the C7N-aminocyclitol family of natural products. EEVS was originally thought to be present only in certain actinomycetes, but analyses of genome sequences showed that it is broadly distributed in both prokaryotes and eukaryotes, including vertebrates. Another SPC, desmethyl-4-deoxygadusol synthase (DDGS), was later discovered as being involved in the biosynthesis of mycosporine-like amino acid sunscreen compounds. Current database annotations are quite unreliable, with many EEVSs reported as DHQS, and most DDGSs reported as EEVS, DHQS, or simply hypothetical proteins. Here, we identify sequence features useful for distinguishing these enzymes, report a crystal structure of a representative DDGS showing the high similarity of the EEVS and DDGS enzymes, identify notable active site differences, and demonstrate the importance of two of these active site residues for catalysis by point mutations. Further, we functionally characterized two representatives of a distinct clade equidistant from known EEVS and known DDGS groups and show them to be authentic EEVSs. Moreover, we document and discuss the distribution of genes that encode EEVS and DDGS in various prokaryotes and eukaryotes, including pathogenic bacteria, plant symbionts, nitrogen-fixing bacteria, myxobacteria, cyanobacteria, fungi, stramenopiles, and animals, suggesting their broad potential biological roles in nature.


ChemBioChem | 2012

The α‐Ketoglutarate/FeII‐Dependent Dioxygenase VldW Is Responsible for the Formation of Validamycin B

Khaled H. Almabruk; Shumpei Asamizu; Ada Chang; Sheril G. Varghese; Taifo Mahmud

From A to B: Through detailed biochemical investigations, we discovered that VldW, an α-ketoglutarate/Fe(II)-dependent dioxygenase, regioselectively hydroxylates validamycin A to validamycin B. The results provide insights into the biosynthesis of hydroxylated validamycins and could be used to control the metabolic outcomes of the validamycin pathway.


ACS Chemical Biology | 2018

Self-Resistance of Natural Product Producers: Past, Present, and Future Focusing on Self-Resistant Protein Variants

Khaled H. Almabruk; Linh K. Dinh; Benjamin Philmus

Nature is a prolific producers of bioactive natural products with an array of biological activities and impact on human and animal health. But with great power comes great responsibility, and the organisms that produce a bioactive compound must be resistant to its biological effects to survive during production/accumulation. Microorganisms, particularly bacteria, have developed different strategies to prevent self-toxicity. Here, we review a few of the major mechanisms including the mechanism of resistance with a focus on self-resistant protein variants, target proteins that contain amino acid substitutions to reduce the binding of the bioactive natural product, and therefore its inhibitory effects are highlighted in depth. We also try to identify some future avenues of research and challenges that need to be addressed.


Biochemistry | 2017

Biochemical Characterization and Structural Basis of Reactivity and Regioselectivity Differences between Burkholderia thailandensis and Burkholderia glumae 1,6-Didesmethyltoxoflavin N-Methyltransferase

Michael K. Fenwick; Khaled H. Almabruk; Steven E. Ealick; Tadhg P. Begley; Benjamin Philmus

Burkholderia glumae converts the guanine base of guanosine triphosphate into an azapteridine and methylates both the pyrimidine and triazine rings to make toxoflavin. Strains of Burkholderia thailandensis and Burkholderia pseudomallei have a gene cluster encoding seven putative biosynthetic enzymes that resembles the toxoflavin gene cluster. Four of the enzymes are similar in sequence to BgToxBCDE, which have been proposed to make 1,6-didesmethyltoxoflavin (1,6-DDMT). One of the remaining enzymes, BthII1283 in B. thailandensis E264, is a predicted S-adenosylmethionine (SAM)-dependent N-methyltransferase that shows a low level of sequence identity to BgToxA, which sequentially methylates N6 and N1 of 1,6-DDMT to form toxoflavin. Here we show that, unlike BgToxA, BthII1283 catalyzes a single methyl transfer to N1 of 1,6-DDMT in vitro. In addition, we investigated the differences in reactivity and regioselectivity by determining crystal structures of BthII1283 with bound S-adenosylhomocysteine (SAH) or 1,6-DDMT and SAH. BthII1283 contains a class I methyltransferase fold and three unique extensions used for 1,6-DDMT recognition. The active site structure suggests that 1,6-DDMT is bound in a reduced form. The plane of the azapteridine ring system is orthogonal to its orientation in BgToxA. In BthII1283, the modeled SAM methyl group is directed toward the p orbital of N1, whereas in BgToxA, it is first directed toward an sp2 orbital of N6 and then toward an sp2 orbital of N1 after planar rotation of the azapteridine ring system. Furthermore, in BthII1283, N1 is hydrogen bonded to a histidine residue whereas BgToxA does not supply an obvious basic residue for either N6 or N1 methylation.


Journal of Natural Products | 2016

Total Synthesis of (±)-Isoperbergins and Correction of the Chemical Structure of Perbergin

Khaled H. Almabruk; Jeff H. Chang; Taifo Mahmud

On the basis of its reported chemical structure, perbergin, a Rhodococcus fascians virulence quencher from the bark of Dalbergia pervillei, and its isomer were synthesized in nine steps with a 13.5% yield. However, the NMR spectra of the synthetic products were inconsistent with those reported in the literature. Re-evaluation of the 1D and 2D NMR spectra of the natural product perbergin revealed that the geranyl moiety of this compound is located at C-6 and has an E-configuration, instead of the reported C-8 geranylation with a Z-configuration. Interestingly, the synthetic isoperbergins demonstrated good antibacterial activity against R. fascians, Mycobacterium smegmatis, and Staphylococcus aureus, but not against the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli.


Journal of the American Chemical Society | 2011

Pseudoglycosyltransferase Catalyzes Nonglycosidic C–N Coupling in Validamycin A Biosynthesis

Shumpei Asamizu; Jongtae Yang; Khaled H. Almabruk; Taifo Mahmud


ChemBioChem | 2012

Inside Cover: The α-Ketoglutarate/FeII-Dependent Dioxygenase VldW Is Responsible for the Formation of Validamycin B (ChemBioChem 15/2012)

Khaled H. Almabruk; Shumpei Asamizu; Ada Chang; Sheril G. Varghese; Taifo Mahmud

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Taifo Mahmud

Oregon State University

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Ada Chang

Oregon State University

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Jongtae Yang

Oregon State University

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