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EcoSal Plus

Domain 3:

Metabolism

Biosynthesis and Regulation of the Branched-Chain Amino Acids†

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  • Authors: Kirsty A. Salmon1, Chin-Rang Yang2, and G. Wesley Hatfield3
  • Editor: Valley Stewart4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, Irvine, CA 92697; 2: Computational Systems Biology and Bioinformatics Laboratory, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Y4.206, Dallas, Texas 75390-7280; 3: Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, Irvine, CA 92697; 4: University of California, Davis, Davis, CA
  • Received 28 September 2005 Accepted 01 December 2005 Published 28 February 2006
  • Address correspondence to G. Wesley Hatfield gwhatfie@uci.edu
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  • Abstract:

    This review focuses on more recent studies concerning the systems biology of branched-chain amino acid biosynthesis, that is, the pathway-specific and global metabolic and genetic regulatory networks that enable the cell to adjust branched-chain amino acid synthesis rates to changing nutritional and environmental conditions. It begins with an overview of the enzymatic steps and metabolic regulatory mechanisms of the pathways and descriptions of the genetic regulatory mechanisms of the individual operons of the isoleucine-leucine-valine () regulon. This is followed by more-detailed discussions of recent evidence that global control mechanisms that coordinate the expression of the operons of this regulon with one another and the growth conditions of the cell are mediated by changes in DNA supercoiling that occur in response to changes in cellular energy charge levels that, in turn, are modulated by nutrient and environmental signals. Since the parallel pathways for isoleucine and valine biosynthesis are catalyzed by a single set of enzymes, and because the AHAS-catalyzed reaction is the first step specific for valine biosynthesis but the second step of isoleucine biosynthesis, valine inhibition of a single enzyme for this enzymatic step might compromise the cell for isoleucine or result in the accumulation of toxic intermediates. The operon-specific regulatory mechanisms of the operons of the regulon are discussed in the review followed by a consideration and brief review of global regulatory proteins such as integration host factor (IHF), Lrp, and CAP (CRP) that affect the expression of these operons.

  • Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5

Key Concept Ranking

Gene Expression and Regulation
0.6942099
Branched-Chain Amino Acid Biosynthesis
0.5388899
Amino Acid Synthesis
0.39137942
Transcription Start Site
0.37605715
Acetyl Coenzyme A
0.36747345
0.6942099

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ecosalplus.3.6.1.5.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.3.6.1.5
2006-02-28
2017-07-21

Abstract:

This review focuses on more recent studies concerning the systems biology of branched-chain amino acid biosynthesis, that is, the pathway-specific and global metabolic and genetic regulatory networks that enable the cell to adjust branched-chain amino acid synthesis rates to changing nutritional and environmental conditions. It begins with an overview of the enzymatic steps and metabolic regulatory mechanisms of the pathways and descriptions of the genetic regulatory mechanisms of the individual operons of the isoleucine-leucine-valine () regulon. This is followed by more-detailed discussions of recent evidence that global control mechanisms that coordinate the expression of the operons of this regulon with one another and the growth conditions of the cell are mediated by changes in DNA supercoiling that occur in response to changes in cellular energy charge levels that, in turn, are modulated by nutrient and environmental signals. Since the parallel pathways for isoleucine and valine biosynthesis are catalyzed by a single set of enzymes, and because the AHAS-catalyzed reaction is the first step specific for valine biosynthesis but the second step of isoleucine biosynthesis, valine inhibition of a single enzyme for this enzymatic step might compromise the cell for isoleucine or result in the accumulation of toxic intermediates. The operon-specific regulatory mechanisms of the operons of the regulon are discussed in the review followed by a consideration and brief review of global regulatory proteins such as integration host factor (IHF), Lrp, and CAP (CRP) that affect the expression of these operons.

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Figures

Image of Figure 1
Figure 1

The enzymes (and their corresponding gene) are red. Enzyme reactions are indicated by arrows. Feedback inhibition/activation patterns are indicated by dashed lines (blue, -leucine; green, -valine; yellow, -isoleucine). Activation is indicated by a plus sign, and inhibition is indicated by a vertical bar.

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 2
Figure 2

This schematic depicts an ordered Bi Bi mechanism because substrate 1 (S) must bind to the enzyme (En) and form a substrate-enzyme intermediate complex (EnS) and release the first product (P) and form the enzyme-intermediate complex (EnX) before the second substrate (S) can bind to the enzyme. Next, the enzyme-bound intermediate is transferred to S, and the free enzyme is released. This is a Ping Pong mechanism because the enzyme shuttles between a free and a substrate-modified intermediate state.

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 3
Figure 3

Conditions described in Fig. 15 were used for the simulations presented here. -Valine was added at a rate sufficient to be maintained at a concentration of 1 mM. The data in panel A show that, as described in the text, excess -valine increases rather than inhibits -isoleucine biosynthesis. The data in panel B show that excess -valine also causes a fourfold increase in the intracellular accumulation of αKB, which is restored to control levels by the extracellular addition of 500 μM -isoleucine. The data in panel C show that the accumulation of αKB observed in the presence of excess -valine coincides with the conversion of nearly 18% of the cellular TDA to a catalytically active R state and that the subsequent extracellular addition of 500 μM -isoleucine reverses this transition to the control level. Presented with permission from reference 43 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 4
Figure 4

Promoters of each operon are indicated by arrows. Lrp-binding sites are shown as green ovals. IlvY-binding sites are shown as blue hexagons. IHF-binding sites are shown as blue rectangles. The CAP-binding site is shown as a red square. The LeuO-binding site is indicated by a purple oval. The location of the gene in the operon is indicated; however, the promoter of this gene has not yet been defined. Adapted from reference 63 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 5
Figure 5

The promoter is indicated by the −35/−10 boxes. The transcription start site is indicated with a +1. The leader peptide-coding region is shown by a shaded box. The four transcript segments that specify the alternative RNA secondary structures are marked by green boxes (boxes 1 to 4). The pause site, causing a temporary halt to transcription, is marked. The terminator is marked by a “t.” The attenuator structure, formed by base pairing of the three and four transcript segments, is marked. The location of the first structural gene of the operon is marked by a yellow box. Beneath the figure are the two possible mRNA products: the upper, shorter mRNA product is the result of attenuation; the longer mRNA product is the result of readthrough of the structural genes.

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 6
Figure 6

(A) attenuator (adapted from reference 99 ). (B) antiterminator (adapted from reference 99 ). (C) attenuator (adapted from reference 100 ). (D) antiterminator (adapted from reference 100 ). (E) attenuator (adapted from reference 101 ). (F) antiterminator (adapted from reference 101 ). The nucleotide sequence of the leader transcripts is shown in black; differences in the LT2 strain are shown in light blue. Leucine codons are shown in red, valine codons are in green, and isoleucine codons are in orange. Alternative RNA stem-loop structures 1:2, 2:3, and 3:4 are labeled. Nucleotide positions are numbered from the start of transcription. The leader polypeptide-coding regions are shaded in gray. Pause sites are indicated ( 102 ).

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 7
Figure 7

(A) When leucine levels are high, the ribosome translates through region 1 (the open reading frame encoding the leader peptide) into region 2 before region 3 is transcribed. Continued transcription leads to the synthesis of region 4 and pairing of regions 3 and 4 to form the attenuator structure, and transcription is terminated. (B) When leucine levels are low, the ribosome pauses at the tandem Leu codons in region 1, but the RNA polymerase continues to transcribe through regions 2 and 3. Formation of the paired structure between regions 2 and 3 preempts pairing of regions 3 and 4 to form the attenuator structure. Thus, transcription proceeds into the structural genes of the operon.

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 8
Figure 8

The product operator sites, designated O and O, are indicated by shaded boxes. The transcriptional initiation sites of the and genes are indicated by arrows. Bases are numbered relative to the transcription initiation site. The −10 and −35 hexamer regions of the and promoters are designated by green boxes () and yellow boxes () (from reference 123 ).

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 9
Figure 9

Substrate binding to a preformed IlvY protein DNA complex relaxes an IlvY protein-induced DNA bend and increases the affinity for RNA polymerase binding nearly 100-fold. Blue hexagons, IlvY protein homodimers; green oval structure, RNA polymerase.

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 10
Figure 10

(A) SIDD profile of pDHΔwt indicating the predicted free energy required for DNA duplex destabilization. () is expressed in kcal/mol/bp as a function of base pair location . The arrow indicates the location of the IHF-binding site in the UAS1 region of the P promoter insert (plasmid base pair positions 4 to 256). (B) Probability, (), of DNA duplex destabilization as a function of base pair location . The arrow indicates the location of the IHF-binding site in the UAS1 region. (C) Close-up SIDD profile [() of pDHΔwt from base pair positions 180 to +1 relative to the P transcriptional start site (base pair positions 76 to 256 in the plasmid)]. Presented with permission from reference 172 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 11
Figure 11

The IHF heterodimer is indicated by the blue oval shape; the SIDD structure is indicated by a green box. See text for description.

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 12
Figure 12

(A) The basal and IHF-activated transcriptional rates determined on topoisomers of pDHΔwt in the absence (red circles) and presence (blue circles) of IHF. (B) The basal and IHF-activated transcriptional rates determined on topoisomers of pSSΔZ in the absence (red circles) and presence (blue circles) of IHF. Arrows indicate DNA templates of the lowest |ΔLk| that demonstrate OsO reactivity in the UAS1 region. Transcriptional rates (means ± standard deviations of three experiments) were normalized by setting the maximum level of transcription for each DNA template in each plot equal to 1.0. Presented with permission from reference 173 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 13
Figure 13

The promoter is indicated by an arrow. The FIS-binding site is shown as a yellow circle. Adapted from reference 63 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 14
Figure 14

Predicted free energies () for duplex destabilization at a superhelical density of σ = 0.05 at base position are expressed in kcal/mol/bp. The positions of relevant promoter features are indicated above the SIDD plot. The transcriptional start site is indicated by an arrow. The 10 and 35 hexanucleotide regions are identified by thin horizontal lines. The discriminator is denoted by a thick horizontal line. The Fis-binding site and first tRNA gene are labeled. Presented with permission from reference 184 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 15
Figure 15

RNA polymerase is represented by a large shaded oval. Fis is represented by a green oval. Open complex formation is represented by a bubble in the duplex DNA (designated by a single line). The strength of open complex formation is indicated by the size of the bubble. The putative cruciform structure is indicated by a stem-loop structure. See text for details. Presented with permission from reference 137 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Image of Figure 16
Figure 16

The abbreviations of enzymes used are as follows: AKI, aspartate kinase I; AKIII, aspartate kinase III; HDHI, homoserine dehydrogenase I; ASD, semialdehyde dehydrogenase; HSK, homoserine kinase; TS, threonine synthase; TDA, threonine deaminase; AHAS, acetohydroxy acid synthase; IR, acetohydroxy acid isomeroreductase; DAD, dihydroxy acid dehydrase; TB, transaminase B; TC, transaminase C; IPMS, α-isopropylmalate synthase; IPMI, α-isopropylmalate isomerase; IPMDH, α-isopropylmalate dehydrogenase. The abbreviations of metabolites used are as follows: Asp, aspartate; AspP, aspartyl phosphate; ASA, aspartate semialdehyde; Hse, homoserine; HseP, homoserine phosphate; Thr, -threonine; Ile, -isoleucine; Val, -valine; Leu, leucine; Glu, -glutamate; Ala, alanine; Pyr, pyruvate; αKB, α-ketobutyrate; αAL, α-acetolactate; αAHB, α-aceto-α,β-hydroxybutyrate; αDHIV, α,β-dihydroxyisovalerate; αDMV, α,β-dihydroxy-β-methylvalerate; αKIV, α-ketoisovalerate; αKMV, α-keto-β-methylvalerate; αKG, α-ketoglutarate; αIPM, α-isopropylmalate; βIPM, β-isopropylmalate; αKIC, α-ketoisocaproate. Ovals represent enzyme molecules. White ovals indicate free enzyme states, and shaded ovals indicate intermediate enzyme states with a function group attached to enzymes. Enzyme reactions are indicated by lines with arrows. Reversible reactions are indicated by gray lines with arrows. Switching between free and intermediate enzyme states as well as switching between AKI-HDHI activities is indicated by double-arrowed dashed lines. Presented with permission from reference 43 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Figure 17

The graphical insets show the approach (minutes) to steady state (μM) synthesis and utilization of the substrates, intermediates, and end products of the pathways. (A) -Threonine biosynthesis starting from aspartate. (B) -Isoleucine, -valine, and -leucine biosyntheses starting from -threonine and pyruvate. These two pathways are connected at Thr on the top right corner of panel A and the bottom left corner of panel B. The intermediates are abbreviated as described in the legend to Fig. 16 . The starting substrates aspartate and pyruvate are supplied at rates to maintain constant levels of 3,600 μM and 1,000 μM, respectively. -Glutamate (Glu) and alanine (Ala), for the transamination reactions are supplied at a rate to maintain constant levels of 2,000 μM each. For the IR reaction, NADPH is supplied at a rate to maintain a constant level of 1,000 μM. For the IPMS reaction, acetyl-CoA is supplied at a rate to maintain a constant level of 1,000 μM. The beginning substrate (aspartate and pyruvate) levels, as well as the end product (-threonine, -isoleucine, -valine, and -leucine) levels, agree with measured intracellular values ( 35 , 197 ). Where available, the ranges of reported values for pathway intermediate and end product levels in cells growing in a glucose minimal salts medium are shown in parentheses (μM) in the inset graphs. Presented with permission from reference 43 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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Figure 18

The simulation conditions described in Fig. 15 were used for the simulations presented here except that a -threonine deaminase feedback-resistant mutant (TDA) was simulated by increasing its for isoleucine to 100,000 μM, and the operon attenuator mutant ( was simulated by increasing TDA, AHAS II, IR, DAD, and TB total enzyme levels 11-fold. The simulation in panel A shows that the effect of the feedback-resistant TDA mutant (TDA) is to allow the positive effector ligands -threonine and -valine to transition nearly 100% of the TDA enzyme to the active R state. The simulation results in panel B show that -isoleucine production in the TDA mutant is five- to sixfold increased. The simulation in panel C demonstrates that, in the TDA K-12 mutant, the intermediate, αKB, accumulates to a level 40-fold higher than in a wild-type K-12 strain; however, when the AHAS II isozyme is restored and the bifunctional enzymes of the -isoleucine and -valine pathways are genetically derepressed 11-fold (), αKB accumulation is relieved (C) and -isoleucine synthesis is increased more than 40-fold over the wild-type K-12 level (D). Presented with permission from reference 43 .

Citation: Salmon K, Yang C, Hatfield G. 2006. Biosynthesis and Regulation of the Branched-Chain Amino Acids†, EcoSal Plus 2006; doi:10.1128/ecosalplus.3.6.1.5
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