Accumulation of Homolanthionine and Activation of a Novel Pathway for Isoleucine Biosynthesis in C<i>orynebacterium glutamicum</i>McbR Deletion Strains

Krömer, Jens O.; Heinzle, Elmar; Schröder, Hartwig; Wittmann, Christoph

doi:10.1128/jb.188.2.609-618.2006

Cited by 46 publications

(38 citation statements)

References 33 publications

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“…Precursors for Thr-and Met-independent Ile biosynthesis in microorganisms include Glu, 2-methylbutyrate, propionate, homolanthionine, and citramalate (Phillips et al, 1972;Kisumi et al, 1977;Monticello et al, 1984;Hochuli et al, 1999;Xu et al, 2004;Krö mer et al, 2006;Risso et al, 2008). Metabolite profiling experiments have shown the presence of citramalate in Arabidopsis (Fiehn et al, 2000;Roessner-Tunali et al, 2003), and it has therefore been proposed that citramalate may also serve as a precursor for Ile biosynthesis in plants (de Kraker et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Arabidopsis Methionineγ-Lyase Is Regulated According to Isoleucine Biosynthesis Needs But Plays a Subordinate Role to Threonine Deaminase

Joshi

Jander

2009

Plant Physiology

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The canonical pathway for isoleucine biosynthesis in plants begins with the conversion of threonine to 2-ketobutyrate by threonine deaminase (OMR1). However, demonstration of methionine g-lyase (MGL) activity in Arabidopsis (Arabidopsis thaliana) suggested that production of 2-ketobutyrate from methionine can also lead to isoleucine biosynthesis. Rescue of the isoleucine deficit in a threonine deaminase mutant by MGL overexpression, as well as decreased transcription of endogenous Arabidopsis MGL in a feedback-insensitive threonine deaminase mutant background, shows that these two enzymes have overlapping functions in amino acid biosynthesis. In mgl mutant flowers and seeds, methionine levels are significantly increased and incorporation of [13 C]Met into isoleucine is decreased, but isoleucine levels are unaffected. Accumulation of free isoleucine and other branched-chain amino acids is greatly elevated in response to drought stress in Arabidopsis. Gene expression analyses, amino acid phenotypes, and labeled precursor feeding experiments demonstrate that MGL activity is upregulated by osmotic stress but likely plays a less prominent role in isoleucine biosynthesis than threonine deaminase. The observation that MGL makes a significant contribution to methionine degradation, particularly in reproductive tissue, suggests practical applications for silencing the expression of MGL in crop plants and thereby increasing the abundance of methionine, a limiting essential amino acid.

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Section: Discussionmentioning

confidence: 99%

Arabidopsis Methionineγ-Lyase Is Regulated According to Isoleucine Biosynthesis Needs But Plays a Subordinate Role to Threonine Deaminase

Joshi

Jander

2009

Plant Physiology

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“…The first report of biologically derived homolanthionine dates back to 1963 in a mutant strain of E. coli (37), and the accumulation of this compound was later reported in other organisms (38,39). In Corynebacterium glutamicum, homolanthionine is an intermediate in a novel pathway for isoleucine synthesis (40). Homolanthionine formation by both rat and human liver CSE by the condensation of homocysteine and homoserine has been reported (41).…”

mentioning

confidence: 99%

H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia

Chiku

Padovani

Zhu

et al. 2009

Journal of Biological Chemistry

434

424

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Although there is a growing recognition of the significance of hydrogen sulfide (H 2 S) as a biological signaling molecule involved in vascular and nervous system functions, its biogenesis and regulation are poorly understood. It is widely assumed that desulfhydration of cysteine is the major source of H 2 S in mammals and is catalyzed by the transsulfuration pathway enzymes, cystathionine ␤-synthase and cystathionine ␥-lyase (CSE). In this study, we demonstrate that the profligacy of human CSE results in a variety of reactions that generate H 2 S from cysteine and homocysteine. The ␥-replacement reaction, which condenses two molecules of homocysteine, yields H 2 S and a novel biomarker, homolanthionine, which has been reported in urine of homocystinuric patients, whereas a ␤-replacement reaction, which condenses two molecules of cysteine, generates lanthionine. Kinetic simulations at physiologically relevant concentrations of cysteine and homocysteine, reveal that the ␣,␤-elimination of cysteine accounts for ϳ70% of H 2 S generation. However, the relative importance of homocysteinederived H 2 S increases progressively with the grade of hyperhomocysteinemia, and under conditions of severely elevated homocysteine (200 M), the ␣,␥-elimination and ␥-replacement reactions of homocysteine together are predicted to account for ϳ90% of H 2 S generation by CSE. Excessive H 2 S production in hyperhomocysteinemia may contribute to the associated cardiovascular pathology.H 2 S is the newest member of a growing list of gaseous signaling molecules that modulate physiological functions (1-3). Concentrations of H 2 S ranging from 50 to 160 M have been reported in the brain (4), where it appears to function as a neuromodulator by potentiating the activity of the N-methyl-Daspartate receptor and by altering induction of long term potentiation in the hippocampus, important for memory and learning (5). H 2 S levels in human plasma are reported to be ϳ50 M, and in vitro studies suggest that it functions as a vasodilator by opening K ATP channels in vascular smooth muscle cells (6).A recent in vivo study has demonstrated the efficacy of H 2 S in attenuating myocardial ischemia-reperfusion injury by protecting mitochondrial function (7). The role of H 2 S in inflammation is suggested by several studies (8 -11); however, the underlying mechanism is unknown. Remarkably, H 2 S can also induce a state of suspended animation in mice by decreasing the metabolic rate and the core body temperature presumably by inhibiting cytochrome c oxidase in the respiratory chain (12).Endogenous H 2 S is presumed to be generated primarily by desulfhydration of cysteine catalyzed by the two pyridoxal phosphate (PLP) 3 -dependent enzymes in the transsulfuration pathway: cystathionine ␤-synthase (CBS) and cystathionine ␥-lyase (CSE) (13,14). In fact, it is widely assumed, based on the reported absences of CSE in the brain (15) and of H 2 S in the brain of CBS knock-out mice (16), that CBS is the primary source of H 2 S in this organ, whereas CSE plays the...

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“…The synthesis of methionine involves complex networks of regulatory interactions and metabolic pathways. Even with over-expressing of almost all genes involved in methionine biosynthesis via deletion of the central repressor McbR, C. glutamicum does not over-produce this amino acid as shown recently, pointing at other (regulatory) mechanisms that are limiting [40]. Due to extended research, complex and efficient [41,42].…”

Section: Biosynthetic Pathways Towards Biotechnology Productsmentioning

confidence: 89%

“…Among the most striking findings was the overexpression of the tkt gene in the PPP encoding transketolase which strongly enhanced tryptophan production by improved supply of the precursor E4P [154,155]. To avoid accumulation of indole, the last intermediate in the tryptophan pathway, due 40 C. Wittmann to a limiting supply of L-serine, the availability of L-serine was improved by amplification of the serA gene for 3-phosphoglycerate dehydrogenase, the key enzyme in the L-serine biosynthesis [156]. A key to increased production was also the deletion of transport systems for aromatic amino acids impairing their uptake from the medium [6].…”

Section: Metabolic Engineering Of Aromatic Amino Acid Productionmentioning

confidence: 99%

Analysis and Engineering of Metabolic Pathway Fluxes in Corynebacterium glutamicum

Wittmann

2010

Biosystems Engineering I

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The Gram-positive soil bacterium Corynebacterium glutamicum was discovered as a natural overproducer of glutamate about 50 years ago. Linked to the steadily increasing economical importance of this microorganism for production of glutamate and other amino acids, the quest for efficient production strains has been an intense area of research during the past few decades. Efficient production strains were created by applying classical mutagenesis and selection and especially metabolic engineering strategies with the advent of recombinant DNA technology. Hereby experimental and computational approaches have provided fascinating insights into the metabolism of this microorganism and directed strain engineering. Today, C. glutamicum is applied to the industrial production of more than 2 million tons of amino acids per year. The huge achievements in recent years, including the sequencing of the complete genome and efficient post genomic approaches, now provide the basis for a new, fascinating era of research -analysis of metabolic and regulatory properties of C. glutamicum on a global scale towards novel and superior bioprocesses.

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Accumulation of Homolanthionine and Activation of a Novel Pathway for Isoleucine Biosynthesis in Corynebacterium glutamicumMcbR Deletion Strains

Cited by 46 publications

References 33 publications

Arabidopsis Methionineγ-Lyase Is Regulated According to Isoleucine Biosynthesis Needs But Plays a Subordinate Role to Threonine Deaminase

Arabidopsis Methionineγ-Lyase Is Regulated According to Isoleucine Biosynthesis Needs But Plays a Subordinate Role to Threonine Deaminase

H2S Biogenesis by Human Cystathionine γ-Lyase Leads to the Novel Sulfur Metabolites Lanthionine and Homolanthionine and Is Responsive to the Grade of Hyperhomocysteinemia

Analysis and Engineering of Metabolic Pathway Fluxes in Corynebacterium glutamicum

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