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Agrobacterium tumefaciens increases cytokinin production in plastids by modifying the biosynthetic pathway in the host plant.

Agrobacterium tumefaciens infects plants and induces the formation of tumors called "crown galls" by integrating the transferred-DNA (T-DNA) region of the Ti-plasmid into the plant nuclear genome. Tumors are formed because the T-DNA encodes enzymes that modify the synthesis of two plant growth hormones, auxin and cytokinin (CK). Here, we show that a CK biosynthesis enzyme, Tmr, which is encoded by the Agrobacterium T-DNA region, is targeted to and functions in plastids of infected plant cells, despite having no typical plastid-targeting sequence. Evidence is provided that Tmr is an adenosine phosphate-isopentenyltransferase (IPT) that creates a new CK biosynthesis bypass by using 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (HMBDP) as a substrate. Unlike in the conventional CK biosynthesis pathway in plants, trans-zeatin-type CKs are produced directly without the requirement for P450 monooxygenase-mediated hydroxylation. Consistent with the plastid localization of Tmr, HMBDP is an intermediate in the methylerythritol phosphate pathway, a plastid-localized biosynthesis route for universal isoprenoid precursors. These results demonstrate that A. tumefaciens modifies CK biosynthesis by sending a key enzyme into plastids of the host plant to promote tumorigenesis.

Adenine Nucleotides↗

Yellow flowers generated by expression of the aurone biosynthetic pathway.

Flower color is most often conferred by colored flavonoid pigments. Aurone flavonoids confer a bright yellow color on flowers such as snapdragon (Antirrhinum majus) and dahlia (Dahlia variabilis). A. majus aureusidin synthase (AmAS1) was identified as the key enzyme that catalyzes aurone biosynthesis from chalcones, but transgenic flowers overexpressing AmAS1 gene failed to produce aurones. Here, we report that chalcone 4'-O-glucosyltransferase (4'CGT) is essential for aurone biosynthesis and yellow coloration in vivo. Coexpression of the Am4'CGT and AmAS1 genes was sufficient for the accumulation of aureusidin 6-O-glucoside in transgenic flowers (Torenia hybrida). Furthermore, their coexpression combined with down-regulation of anthocyanin biosynthesis by RNA interference (RNAi) resulted in yellow flowers. An Am4'CGT-GFP chimeric protein localized in the cytoplasm, whereas the AmAS1(N1-60)-RFP chimeric protein was localized to the vacuole. We therefore conclude that chalcones are 4'-O-glucosylated in the cytoplasm, their 4'-O-glucosides transported to the vacuole, and therein enzymatically converted to aurone 6-O-glucosides. This metabolic pathway is unique among the known examples of flavonoid, including anthocyanin biosynthesis because, for all other compounds, the carbon backbone is completed before transport to the vacuole. Our findings herein not only demonstrate the biochemical basis of aurone biosynthesis but also open the way to engineering yellow flowers for major ornamental species lacking this color variant.

Antirrhinum↗

Structure of the TDP-epi-vancosaminyltransferase GtfA from the chloroeremomycin biosynthetic pathway.

During the biosynthesis of the vancomycin-class antibiotic chloroeremomycin, TDP-epi-vancosaminyltransferase GtfA catalyzes the attachment of 4-epi-vancosamine from a TDP donor to the beta-OHTyr-6 of the aglycone cosubstrate. Glycosyltransferases from this pathway are potential tools for the combinatorial design of new antibiotics that are effective against vancomycin-resistant bacterial strains. These enzymes are members of the GT-B glycosyltransferase superfamily, which share a homologous bidomain topology. We present the 2.8-A crystal structures of GtfA complexes with vancomycin and the natural monoglycosylated peptide substrate, representing the first direct observation of acceptor substrate binding among closely related glycosyltransferases. The acceptor substrates bind to the N-terminal domain such that the aglycone substrate's reactive hydroxyl group hydrogen bonds to the side chains of Ser-10 and Asp-13, thus identifying these as residues of potential catalytic importance. As well as an open form of the enzyme, the crystal structures have revealed a closed form in which a TDP ligand is bound at a donor substrate site in the interdomain cleft, thereby illustrating not only binding interactions, but the conformational changes in the enzyme that accompany substrate binding.

Aspartic Acid↗

Chitin biosynthesis during Blastocladiella zoospore germination: evidence that the hexosamine biosynthetic pathway is post-translationally activated during cell differentiation.

De novo construction of a chitinous cell wall accompanies Blastocladiella emersonii zoospore germination. At least an order of magnitude increase in total hexosamine occurs during germination. This increase is into polymer (chitin) and occurs on schedule in the presence of cycloheximide. Uridine-5'-diphospho-N-acetylglucosamine (UDPGlcNAc), both the end product of hexosamine biosynthesis and a substrate for chitin biosynthesis, is a potent inhibitor of the activity of the first pathway-specific enzyme of hexosamine biosynthesis in zoospore extracts. Certain uridine nucleotides, not perceptibly influencing the activity of the first enzyme per se, counteract the inhibitory effects of UDPGlcNAc. The concentration of UDPGlcNAc in the zoospore is sufficient to act as an inhibitor of the enzyme, but the amount of UDPGlcNAc is sufficient, by over an order of magnitude, to account for the chitin synthesized during germination. Both the production of UDPGlcNAc and its utilization for chitin synthesis appear to be post-translationally regulated in zoospores and during zoospore germination.

Blastocladiella↗

Regulation of the hexosamine biosynthetic pathway in the water mold Blastocladiella emersonii: Sensitivity to endproduct inhibition is dependent upon the life cycle phase.

Chitin, a homopolymer of N-acetylglucosamine (GlcNAc), is the major macromolecular constituent of Blastocladiella emersonii cell walls. Zoospores do not possess a wall nor do they contain sufficient total hexosamine to account for the chitin content of the wall abruptly formed during germination. UDPGlcNAc, both the endproduct of hexosamine biosynthesis and the substrate for chitin synthesis, is present in zoospores in sufficient concentration to inhibit the first hexosamine pathway-specific enzyme activity. Net chitin accumulates in register with dry weight during exponential growth, but does not accumulate appreciably during the succeeding sporulation phase. Predicted relationships among net rates of chitin synthesis, UDPGlcNAc concentrations, and UDP plus UTP concentrations throughout the life cycle are explored, as are the assumptions upon which the predictions were based. We find that the sensitivity of the first hexosamine pathway-specific enzyme to endproduct inhibition is not constant throughout the life cycle; sensitivity is very high in the zoospore phase, decreases dramatically during germination, remains very low through the growth phase, and increases gradually to the zoospore level during sporulation. The organism appears to have evolved endproduct regulation in this case as an adaptation to "hard-times" phases of the life cycle-i.e., as a safeguard against overproduction of end product (UDPGlcNAc) when its utilization in cell wall (specifically chitin) synthesis is curtailed. Conversely, the organism effectively discards this mode of regulation during "good times," when the demands for end product are evidently greater than endproduct inhibition would otherwise permit.

Journal Article↗

Enkephalin biosynthetic pathway: proteins of 8000 and 14,000 daltons in bovine adrenal medulla.

Two [Met]enkephalin-containing polypeptides have been purified from extracts of bovine and adrenal chromaffin granules. One is 8000 daltons in size and contains the enkephalin sequence at the carboxy terminus. The other (14,000 daltons) has two internal enkephalin sequences and a third sequence at the carboxy terminus. All of these sequences can be released by trypsin, indicating a possible enkephalin precursor role for the polypeptides.

Adrenal Medulla↗

Enkephalin biosynthetic pathway: a 5300-dalton adrenal polypeptide that terminates at its COOH end with the sequence [Met]enkephalin-Arg-Gly-Leu-COOH.

An enkephalin-containing polypeptide of 5300 daltons has been isolated from extracts of bovine adrenal medulla and purified to homogeneity, and its sequence has been determined by a combination of automated Edman degradation and enzymatic time-course hydrolysis. The polypeptide contains a single [Met]enkephalin sequence followed by Arg-Gly-Leu-COOH, which forms the COOH terminus of the molecule. The enkephalin sequence is preceded by a Lys-Arg linkage, typical of prohormone cleavage sites. Posttranslational processing of the polypeptide at this site would lead to release of the octapeptide [Met]enkephalin-Arg6-Gly7-Leu8.

Amino Acid Sequence↗

Evolution in biosynthetic pathways: two enzymes catalyzing consecutive steps in methionine biosynthesis originate from a common ancestor and possess a similar regulatory region.

The metC gene of Escherichia coli K-12 was cloned and the nucleotide sequence of the metC gene and its flanking regions was determined. The translation initiation codon was identified by sequencing the NH2-terminal part of beta-cystathionase, the MetC gene product. The metC gene (1185 nucleotides) encodes a protein having 395 amino acid residues. The 5' noncoding region was found to contain a "Met box" homologous to sequences suggestive of operator structures upstream from other methionine genes that are controlled by the product of the pleiotropic regulatory metJ gene. The deduced amino acid sequence of beta-cystathionase showed extensive homology with that of the MetB protein (cystathionine gamma-synthase) that catalyzes the preceding step in methionine biosynthesis. The homology strongly suggests that the structural genes for the MetB and MetC proteins evolved from a common ancestral gene.

Amino Acid Sequence↗

Endogenous gibberellins in Arabidopsis thaliana and possible steps blocked in the biosynthetic pathways of the semidwarf ga4 and ga5 mutants.

Twenty gibberellins (GAs) have been identified in extracts from shoots of the Landsberg erecta line of Arabidopsis thaliana by full-scan gas chromatography-mass spectrometry and Kovats retention indices. Eight of them are members of the early-13-hydroxylation pathway (GA53, GA44, GA19, GA17, GA20, GA1, GA29, and GA8), six are members of the early-3-hydroxylation pathway (GA37, GA27, GA36, GA13, GA4, and GA34), and the remaining six are members of the non-3,13-hydroxylation pathway (GA12, GA15, GA24, GA25, GA9, and GA51). Seven of these GAs were quantified in the Landsberg erecta line of Arabidopsis and in the semidwarf ga4 and ga5 mutants by gas chromatography-selected ion monitoring (SIM) using internal standards. The relative levels of the remaining 13 GAs were compared by the use of ion intensities only. In comparison with the Landsberg erecta line, the ga4 mutant had reduced levels of the 3-hydroxy- and 3,13-dihydroxy-GAs, and it accumulated the 13-hydroxy-GAs, except GA53, and the non-3,13-hydroxy-GAs, except GA12. The GA4 gene encodes, therefore, a protein with 3 beta-hydroxylation activity. The ga5 mutant had reduced levels of the C19-GAs, which indicates that the product of the GA5 gene catalyzes the elimination of C-20 at the aldehyde level. The ga5 mutant also had increased levels of certain C20-GAs, which indicates existence of an additional control, possibly hydroxylation of C-20. The growth-response data, as well as the accumulation of GA9 in the ga4 mutant, indicate that GA9 is not active in Arabidopsis, but it must be 3 beta-hydroxylated to GA4 to become bioactive. It is concluded that the reduced levels of the 3 beta-hydroxy-GAs, GA1 and GA4, are the cause of the semidwarf growth habit of both mutants.

Chromatography, High Pressure Liquid↗

Arabidopsis thaliana auxotrophs reveal a tryptophan-independent biosynthetic pathway for indole-3-acetic acid.

We used tryptophan auxotrophs of the dicot Arabidopsis thaliana (wall cress) to determine whether tryptophan has the capacity to serve as a precursor to the auxin, indole-3-acetic acid (IAA). Quantitative gas chromatography-selected ion monitoring-mass spectrometry (GC-SIM-MS) revealed that the trp2-1 mutant, which is defective in the conversion of indole to tryptophan, accumulated amide- and ester-linked IAA at levels 38-fold and 19-fold, respectively, above those of the wild type. Tryptophan and free IAA were isolated from the trp2-1 mutant grown in the presence of [15N]anthranilate and [2H5]tryptophan, and the relative 15N and 2H5 enrichments of tryptophan and IAA were determined via GC-SIM-MS. The 15N enrichment of tryptophan, 13% +/- 4%, was less than the 15N enrichment of the IAA pool, 39% +/- 4%; therefore, IAA biosynthesis occurs via a tryptophan-independent pathway. The amount of 2H5 incorporated by the plant into IAA from tryptophan (9% +/- 4%) was low and only slightly above the level of spontaneous, nonenzymatic conversion of [2H5]tryptophan to [2H5]IAA. These results show that the dicot Arabidopsis is similar to the monocot Zea mays in that the major route of IAA biosynthesis does not occur through tryptophan.

Arabidopsis↗

Substrate specificity of the dolichol phosphate mannose: glucosaminyl phosphatidylinositol alpha1-4-mannosyltransferase of the glycosylphosphatidylinositol biosynthetic pathway of African trypanosomes.

The biosynthesis of glycosylphosphatidylinositol (GPI) precursors in Trypanosoma brucei involves the D-mannosylation of D-GlcN alpha 1-6-D-myo-inositol-1-PO4-sn-1,2-diacylglycerol (GlcN-PI). An assay for the first mannosyltransferase of the pathway, Dol-P-Man:GlcN-PI alpha 1-4-mannosyltransferase, is described. Analysis of the acceptor specificity revealed (a) that the enzyme requires the myo-inositol residue of the GlcN-PI substrate have the D configuration; (b) that the enzyme requires the presence of the NH2 group of the D-GlcN residue; (c) that GlcNAc-PI is more efficiently presented to the enzyme than GlcN-PI, suggesting a degree of substrate channelling via the preceding GlcNAc-PI de-N-acetylase enzyme; (d) that the fatty acid and phosphoglycerol components of the phosphatidyl moiety are important for enhancing substrate presentation and substrate recognition, respectively; and (e) that D-GlcN alpha 1-6-D-myo-inositol is the minimum structure that can support detectable acceptor activity. Analysis of the donor specificity revealed that short chain (C5 and C15) analogues of dolichol phosphate can act as substrates for the trypanosomal dolichol-phosphomannose synthetase, whereas the corresponding mannopyranosides cannot act as donors for the Dol-P-Man:GlcN-PI alpha 1-4-mannosyltransferase.

Animals↗

ApbA, the ketopantoate reductase enzyme of Salmonella typhimurium is required for the synthesis of thiamine via the alternative pyrimidine biosynthetic pathway.

The apbA gene of Salmonella typhimurium was shown to encode ketopantoic acid reductase. ApbA was purified from crude cell-free extracts to greater than 95% homogeneity after two chromatographic steps. N-terminal amino acid sequencing (first 15 amino acids) and Western blot analysis confirmed the isolated protein was ApbA. The functional protein was a monomer with a molecular mass of 31.1 kDa. Optimal reaction conditions for the reduction of ketopantoic acid were established at a pH of 6.25, and a temperature of 42 degreesC. The preferred electron source was NADPH, and the apparent Km constants of the enzyme for NADPH and ketopantoic acid were determined to be 0.776 +/- 0.09 mM and 0.742 +/- 0.01 mM, respectively. The homogeneous enzyme had a specific activity of 64.3.

Alcohol Oxidoreductases↗

Activities of recombinant human cytochrome P450c27 (CYP27) which produce intermediates of alternative bile acid biosynthetic pathways.

The primary physiological significance of cytochrome P450c27 (CYP27) has been associated with its role in the degradation of the side chain of C27 steroids in the hepatic bile acid biosynthesis pathway, which begins with 7alpha-hydroxylation of cholesterol in liver. However, recognition that in humans P450c27 is a widely or ubiquitously expressed mitochondrial P450, and that there are alternative pathways of bile acid synthesis which begin with 27-hydroxylation of cholesterol catalyzed by P450c27, suggests the need to reevaluate the role of this enzyme and its catalytic properties. 27-Hydroxycholesterol was thought to be the only product formed upon reaction of P450c27 with cholesterol. However, the present study demonstrates that recombinant human P450c27 is also able to further oxidize 27-hydroxycholesterol giving first an aldehyde and then 3beta-hydroxy-5-cholestenoic acid. Kinetic data indicate that in a reconstituted system, after 27-hydroxycholesterol is formed from cholesterol, it is released from the P450 and then competes with cholesterol for reentry the enzyme active site for further oxidation. Under subsaturating substrate concentrations, the efficiencies of oxidation of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenal to the acid by human P450c27 are greater than the efficiency of hydroxylation of cholesterol to 27-hydroxycholesterol indicating that the first hydroxylation step in the overall conversion of cholesterol into 3beta-hydroxy-5-cholestenoic acid is rate-limiting. Interestingly, 3beta-hydroxy-5-cholestenoic acid was found to be further metabolized by the recombinant human P450c27, giving two monohydroxylated products with the hydroxyl group introduced at different positions on the steroid nucleus.

Bile Acids and Salts↗

Structure and mechanism of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase. An enzyme in the mevalonate-independent isoprenoid biosynthetic pathway.

The enzyme 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) synthase catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) to MECDP, a highly unusual cyclodiphosphate-containing intermediate on the mevalonate-independent pathway to isopentenyl diphosphate and dimethylallyl diphosphate. We now report two x-ray crystal structures of MECDP synthase refined to 2.8-A resolution. The first structure contains a bound Mn(2+) cation, and the second structure contains CMP, MECDP, and Mn(2+). The protein adopts a homotrimeric quaternary structure built around a central hydrophobic cavity and three externally facing active sites. Each of these active sites is located between two adjacent monomers. A tetrahedrally arranged transition metal binding site, potentially occupied by Mn(2+), sits at the base of the active site cleft. A phosphate oxygen of MECDP and the side chains of Asp(8), His(10), and His(42) occupy the metal ion coordination sphere. These structures reveal for the first time the structural determinants underlying substrate, product, and Mn(2+) recognition and the likely catalytic mechanism accompanying the biosynthesis of the cyclodiphosphate-containing isoprenoid precursor, MECDP.

Aspartic Acid↗

Recruitment of a foreign quinone into the A1 site of photosystem I. Altered kinetics of electron transfer in phylloquinone biosynthetic pathway mutants studied by time-resolved optical, EPR, and electrometric techniques.

Interruption of the menA or menB gene in Synechocystis sp. PCC 6803 results in the incorporation of a foreign quinone, termed Q, into the A(1) site of photosystem I with a number of experimental indicators identifying Q as plastoquinone-9. A global multiexponential analysis of time-resolved optical spectra in the blue region shows the following three kinetic components: 1) a 3-ms lifetime in the absence of methyl viologen that represents charge recombination between P700(+) and an FeS(-) cluster; 2) a 750-microseconds lifetime that represents electron donation from an FeS(-) cluster to methyl viologen; and 3) an approximately 15-microseconds lifetime that represents an electrochromic shift of a carotenoid pigment. Room temperature direct detection transient EPR studies of forward electron transfer show a spectrum of P700(+) Q(-) during the lifetime of the spin polarization and give no evidence of a significant population of P700(+) FeS(-) for t </= 2-3 microseconds. The UV difference spectrum measured 5 microseconds after a flash shows a maximum at 315 nm, a crossover at 280 nm, and a minimum at 255 nm as well as a shoulder at 290-295 nm, all of which are characteristic of the plastoquinone-9 anion radical. Kinetic measurements that monitor Q at 315 nm show a major phase of forward electron transfer to the FeS clusters with a lifetime of approximately 15 microseconds, which matches the electrochromic shift at 485 nm of the carotenoid, as well as an minor phase with a lifetime of approximately 250 microseconds. Electrometric measurements show similar biphasic kinetics. The slower kinetic phase can be detected using time-resolved EPR spectroscopy and has a spectrum characteristic of a semiquinone anion radical. We estimate the redox potential of plastoquinone-9 in the A(1) site to be more oxidizing than phylloquinone so that electron transfer from Q(-) to F(X) is thermodynamically unfavorable in the menA and menB mutants.

Alkyl and Aryl Transferases↗

Selective interaction of triazole derivatives with DWF4, a cytochrome P450 monooxygenase of the brassinosteroid biosynthetic pathway, correlates with brassinosteroid deficiency in planta.

Brassinazole, a synthetic chemical developed in our laboratory, is a triazole-type brassinosteroid biosynthesis inhibitor that induces dwarfism in various plant species. The target sites of brassinazole were investigated by chemical analyses of endogenous brassinosteroids (BRs) in brassinazole-treated Catharanthus roseus cells. The levels of castasterone and brassinolide in brassinazole-treated plant cells were less than 6% of the levels in untreated cells. In contrast, campestanol and 6-oxocampestanol levels were increased, and levels of BR intermediates with hydroxy groups on the side chains were reduced, suggesting that brassinazole treatment reduced BR levels by inhibiting the hydroxylation of the C-22 position. DWF4, which is an Arabidopsis thaliana cytochrome P450 isolated as a putative steroid 22-hydroxylase, was expressed in Escherichia coli, and the binding affinity of brassinazole and its derivatives to the recombinant DWF4 were analyzed. Among several triazole derivatives, brassinazole had both the highest binding affinity to DWF4 and the highest growth inhibitory activity. The binding affinity and the activity for inhibiting hypocotyl growth were well correlated among the derivatives. In brassinazole-treated A. thaliana, the CPD gene involved in BR biosynthesis was induced within 3 h, most likely because of feedback activation caused by the reduced levels of active BRs. These results indicate that brassinazole inhibits the hydroxylation of the C-22 position of the side chain in BRs by direct binding to DWF4 and that DWF4 catalyzes this hydroxylation reaction.

Arabidopsis Proteins↗

Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones.

The cDNA of a novel human glutathione transferase (GST) of the Alpha class was cloned, and the corresponding protein, denoted GST A3-3, was heterologously expressed and characterized. GST A3-3 was found to efficiently catalyze obligatory double-bond isomerizations of Delta(5)-androstene-3,17-dione and Delta(5)-pregnene-3,20-dione, precursors to testosterone and progesterone, respectively, in steroid hormone biosynthesis. The catalytic efficiency (k(cat)/K(m)) with Delta(5)-androstene-3,17-dione was determined as 5 x 10(6) m(-1) s(-1), which is considerably higher than with any other GST substrate tested. The rate of acceleration afforded by GST A3-3 is 6 x 10(8) based on the ratio between k(cat) and the rate constant for the nonenzymatic isomerization of Delta(5)-androstene-3,17-dione. Besides being high in absolute numbers, the k(cat)/K(m) value of GST A3-3 exceeds by a factor of approximately 230 that of 3beta-hydroxysteroid dehydrogenase/isomerase, the enzyme generally considered to catalyze the Delta(5)-Delta(4) double-bond isomerization. Furthermore, GSTA3-specific polymerase chain reaction analysis of cDNA libraries from various tissues showed a message only in those characterized by active steroid hormone biosynthesis, indicating a selective expression of GST A3-3 in these tissues. Based on this finding and the high activity with steroid substrates, we propose that GST A3-3 has evolved to catalyze isomerization reactions that contribute to the biosynthesis of steroid hormones.

Amino Acid Sequence↗