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At least 19 records

Pyruvate, phosphate dikinase regulatory protein impacts light response of C4 photosynthesis in Setaria viridis

In C4 plants, the pyruvate (Pyr), phosphate dikinase regulatory protein (PDRP) regulates the activity of the C4 pathway enzyme Pyr, phosphate dikinase (PPDK) in a light-/dark-dependent manner. The importance of this regulatory action to C4 pathway function and overall C4 photosynthesis is unknown. To resolve this question, we assessed in vivo PPDK phospho-regulation and whole leaf photophysiology in a CRISPR–Cas9 PDRP knockout (KO) mutant of the NADP-ME C4 grass green millet (Setaria viridis). PDRP enzyme activity was undetectable in leaf extracts from PDRP KO lines. Likewise, PPDK phosphorylated at the PDRP-regulatory Thr residue was immunologically undetectable in leaf extracts. PPDK enzyme activity in rapid leaf extracts was constitutively high in the PDRP KO lines, irrespective of light or dark pretreatment of leaves. Gas exchange analysis of net CO2 assimilation revealed PDRP KO leaves had markedly slower light induction kinetics when leaves transition from dark to high-light or low-light to high-light. In the initial 30 min of the light induction phase, KO leaves had an ~15% lower net CO2 assimilation rate versus the wild-type (WT). Despite the impaired slower induction kinetics, we found growth and vigor of the KO lines to be visibly indistinguishable from the WT when grown in normal air and under standard growth chamber conditions. However, the PDRP KO plants grown under a fluctuating light regime exhibited a gradual multi-day decline in Fv/Fm, indicative of progressive photosystem II damage due to the absence of PDRP. Collectively, our results demonstrate that one of PDRP’s functions in C4 photosynthesis is to ensure optimal photosynthetic light induction kinetics during dynamic changes in incident light.

Plant Sciences↗

Multiple highly expressed phospho enol pyruvate carboxylase genes have divergent enzyme kinetic properties in two C4 grasses

Abstract Background and Aims Phosphoenolpyruvate (PEP) carboxylase (PEPC) catalyses the irreversible carboxylation of PEP with bicarbonate to produce oxaloacetate. This reaction powers the carbon-concentrating mechanism (CCM) in plants that perform C4 photosynthesis. This CCM is generally driven by a single PEPC gene product that is highly expressed in the cytosol of mesophyll cells. We found two C4 grasses, Panicum miliaceum and Echinochloa colona, that each have two highly expressed PEPC genes. We characterized the kinetic properties of the two most abundant PEPCs in E. colona and P. miliaceum to better understand how the enzyme’s amino acid structure influences its function. Methods Coding sequences of the two most abundant PEPC proteins in E. colona and P. miliaceum were synthesized by GenScript and were inserted into bacteria expression plasmids. Point mutations resulting in substitutions at conserved amino acid residues (e.g. N-terminal serine and residue 890) were created via site-directed PCR mutagenesis. The kinetic properties of semi-purified plant PEPCs from Escherichia coli were analysed using membrane-inlet mass spectrometry and a spectrophotometric enzyme-coupled reaction. Key Results The two most abundant P. miliaceum PEPCs (PmPPC1 and PmPPC2) have similar sequence identities (>95 %), and as a result had similar kinetic properties. The two most abundant E. colona PEPCs (EcPPC1 and EcPPC2) had identities of ~78 % and had significantly different kinetic properties. The PmPPCs and EcPPCs had different responses to allosteric inhibitors and activators, and substitutions at the conserved N-terminal serine and residue 890 resulted in significantly altered responses to allosteric regulators. Conclusions The two, significantly expressed C4Ppc genes in P. miliaceum were probably the result of genomes combining from two closely related C4Panicum species. We found natural variation in PEPC’s sensitivity to allosteric inhibition that seems to bypass the conserved 890 residue, suggesting alternative evolutionary pathways for increased malate tolerance and other kinetic properties.

DiMario, Robert J. (ORCID:0000000250566868)↗

Pyruvate ingestion for 7 days does not improve aerobic performance in well-trained individuals

The purposes of the present studies were to test the hypotheses that lower dosages of oral pyruvate ingestion would increase blood pyruvate concentration and that the ingestion of a commonly recommended dosage of pyruvate (7 g) for 7 days would enhance performance during intense aerobic exercise in well-trained individuals. Nine recreationally active subjects (8 women, 1 man) consumed 7, 15, and 25 g of pyruvate and were monitored for a 4-h period to determine whether blood metabolites were altered. Pyruvate consumption failed to significantly elevate blood pyruvate, and it had no effect on indexes of carbohydrate (blood glucose, lactate) or lipid metabolism (blood glycerol, plasma free fatty acids). As a follow-up, we administered 7 g/day of either placebo or pyruvate, for a 1-wk period to seven, well-trained male cyclists (maximal oxygen consumption, 62.3 +/- 3.0 ml. kg(-1). min(-1)) in a randomized, double-blind, crossover trial. Subjects cycled at 74-80% of their maximal oxygen consumption until exhaustion. There was no difference in performance times between the two trials (placebo, 91 +/- 9 min; pyruvate, 88 +/- 8 min). Measured blood parameters (insulin, peptide C, glucose, lactate, glycerol, free fatty acids) were also unaffected. Our results indicate that oral pyruvate supplementation does not increase blood pyruvate content and does not enhance performance during intense exercise in well-trained cyclists.

Randomized Controlled Trial↗

Rubisco supplies pyruvate for the 2- C -methyl-D-erythritol-4-phosphate pathway

RIBULOSE-1,5-BISPHOSPHATE CARBOXYLASE/OXYGENASE (Rubisco) produces pyruvate in the chloroplast through β-elimination of the aci-carbanion intermediate. Here we show that this side reaction supplies pyruvate for isoprenoid, fatty acid and branched-chain amino acid biosynthesis in photosynthetically active tissue. 13 C labelling studies of intact Arabidopsis plants demonstrate that the total carbon commitment to pyruvate is too large for phosphoenolpyruvate to serve as a precursor. Low oxygen stimulates Rubisco carboxylase activity and increases pyruvate production and flux through the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway, which supplies the precursors for plastidic isoprenoid biosynthesis. Metabolome analysis of mutants defective in phosphoenolpyruvate or pyruvate import and biochemical characterization of isolated chloroplasts further support Rubisco as the main source of pyruvate in chloroplasts. Seedlings incorporated exogenous, 13 C-labelled pyruvate into MEP pathway intermediates, while adult plants did not, underscoring the developmental transition in pyruvate sourcing. Rubisco β-elimination leading to pyruvate constituted 0.7% of the product profile in in vitro assays, which translates to 2% of the total carbon leaving the Calvin–Benson–Bassham cycle. These insights solve the “pyruvate paradox”, improve the fit of metabolic models for central metabolism and connect the MEP pathway directly to carbon assimilation.

Plant physiology↗

Finding Evidence of a Prebiotic Pyruvate Reaction Network in Meteorites

The organic compounds of carbonaceous chondrites are structurally diverse products of the prolonged abiotic chemistry that occurred before and during the early stages of the solar system. They also represent the types of prebiotic compounds that may have participated in chemical evolutionary processes that gave rise to life. Pyruvic acid is a key component of primary metabolism that has recently been found in carbonaceous chondrites. Its prominence in biology has inspired us to explore its chemistry and possible role in the origin of metabolism. Our laboratory investigations have found that pyruvate (the ionized form of pyruvic acid) can serve as a single-source reactant to generate what we term a pyruvate reaction network (PRN). The core of the PRN is driven by pyruvate aldol polymerization and decay reactions. These decay reactions lead to the production of stable and unstable compounds which include mono, di, and tricarboxylic acids and a variety of keto acids. Importantly, many of these reactions apparently lead back to pyruvate, establishing a feedback process. Finding evidence of this reaction network in meteorites would establish that the chemistry of pyruvate did occur in a prebiotic environment and indeed many of the known compounds found in pyruvate reaction mixtures were detected in the Murchison and Murray meteorites. However, multiple synthetic origins, not tied to pyruvate chemistry, might also explain their meteoritic presence. Thus finding compounds unique to the PRN, such as reaction intermediates, would provide stronger evidence in support of its prebiotic relevance. The identity of these intermediates can only be con-firmed by acquiring chemical standards, however, as most are not available commercially, we engaged in extensive chemical synthesis. Obtaining these standards also provides the opportunity to study their subsequent chemistry and roles in the PRN.

Rios, A. C.↗

Finding Evidence of a Prebiotic Pyruvate Reaction Network in Meteorites

The organic compounds of carbonaceous chondrites are structurally diverse products of the prolonged abiotic chemistry that occurred before and during the early stages of the solar system. They also represent the types of prebiotic compounds that may have participated in chemical evolutionary processes that gave rise to life. Pyruvic acid is a key component of primary metabolism that has recently been found in carbonaceous chondrites. Its prominence in biology has inspired us to explore its chemistry and possible role in the origin of metabolism. Our laboratory investigations have found that pyruvate (the ionized form of pyruvic acid) can serve as a single-source reactant to generate what we term a pyruvate reaction network (PRN). The core of the PRN is driven by pyruvate aldol polymerization and decay reactions. These decay reactions lead to the production of stable and unstable compounds which include mono, di, and tricarboxylic acids and a variety of keto acids. Importantly, many of these reactions apparently lead back to pyruvate, establishing a feedback process. Finding evidence of this reaction network in meteorites would establish that the chemistry of pyruvate did occur in a prebiotic environment and indeed many of the known compounds found in pyruvate reaction mixtures were detected in the Murchison and Murray meteorites. However, multiple synthetic origins, not tied to pyruvate chemistry, might also explain their meteoritic presence. Thus finding compounds unique to the PRN, such as reaction intermediates, would provide stronger evidence in support of its prebiotic relevance. The identity of these intermediates can only be confirmed by acquiring chemical standards, however, as most are not available commercially, we engaged in extensive chemical synthesis. Obtaining these standards also provides the opportunity to study their subsequent chemistry and roles in the PRN.

Rios, Andro↗

Structural Basis for "Flip-Flop" Action of Human Pyruvate Dehydrogenase

The derivative of vitamin B1, thiamin pyrophosphate is a cofactor of pyruvate dehydrogenase, a component enzyme of the mitochondrial pyruvate dehydrogenase multienzyme complex that plays a major role in directing energy metabolism in the cell. This cofactor is used to cleave the C(sup alpha)-C(=O) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase. In alpha(sub 2)beta(sub 2)-tetrameric human pyruvate dehydrogenase, there are two cofactor binding sites, each of them being a center of independently conducted, although highly coordinated enzymatic reactions. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites can now be understood based on the recently determined crystal structure of the holo-form of human pyruvate dehydrogenase at 1.95A resolution. The structure of pyruvate dehydrogenase was determined using a combination of MAD phasing and molecular replacement followed by rounds of torsion-angles molecular-dynamics simulated-annealing refinement. The final pyruvate dehydrogenase structure included coordinates for all protein amino acids two cofactor molecules, two magnesium and two potassium ions, and 742 water molecules. The structure was refined to R = 0.202 and R(sub free) = 0.244. Our structural analysis of the enzyme folding and domain assembly identified a simple mechanism of this protein motion required for the conduct of catalytic action.

Ciszak, Ewa↗

Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation of the Hyperpolarized Ketone and Hemiketal Forms of Allyl [1- 13 C]Pyruvate

13 C hyperpolarized pyruvate is an emerging MRI contrast agent for sensing molecular events in cancer and other diseases with aberrant metabolic pathways. This metabolic contrast agent can be produced via several hyperpolarization techniques. Despite remarkable success in research settings, widespread clinical adoption faces substantial roadblocks because the current sensing technology utilized to sense this contrast agent requires the excitation of 13 C nuclear spins that also need to be synchronized with MRI field gradient pulses. Here, we demonstrate sensing of hyperpolarized allyl [1- 13 C]pyruvate via the stimulated emission of radiation that mitigates the requirements currently blocking broader adoption. Specifically, 13 C Radiofrequency Amplification by Stimulated Emission of Radiation ( 13 C RASER) was obtained after pairwise addition of parahydrogen to a pyruvate precursor, detected in a commercial inductive detector with a quality factor (Q) of 32 for sample concentrations as low as 0.125 M with 13 C polarization of 4%. Moreover, parahydrogen-induced polarization allowed for the preparation of a mixture of ketone and hemiketal forms of hyperpolarized allyl [1- 13 C]pyruvate, which are separated by 10 ppm in 13 C NMR spectra. This is a good model system to study the simultaneous 13 C RASER signals of multiple 13 C species. This system models the metabolic production of hyperpolarized [1- 13 C]lactate from hyperpolarized [1- 13 C]pyruvate, which has a similar chemical shift difference. Our results show that 13 C RASER signals can be obtained from both species simultaneously when the emission threshold is exceeded for both species. On the other hand, when the emission threshold is exceeded only for one of the hyperpolarized species, 13 C stimulated emission is confined to this species only, therefore enabling the background-free detection of individual hyperpolarized 13 C signals. Furthermore, the reported results pave the way to novel sensing approaches of 13 C hyperpolarized pyruvate, potentially unlocking hyperpolarized 13 C MRI on virtually any MRI system–an attractive vision for the future molecular imaging and diagnostics.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Mycobacterium tuberculosis CitA activity is modulated by cysteine oxidation and pyruvate binding

As an adaptation for survival during infection, Mycobacterium tuberculosis becomes dormant, reducing its metabolism and growth. Two types of citrate synthases have been identified in Mycobacterium tuberculosis, GltA2 and CitA. Previous work shows that overexpression of CitA, the secondary citrate synthase, stimulates the growth of Mycobacterium tuberculosis under hypoxic conditions without showing accumulation of triacylglycerols and makes mycobacteria more sensitive to antibiotics, suggesting that CitA may play a role as a metabolic switch during infection and may be an interesting TB drug target. To assess the druggability and possible mechanisms of targeting CitA with small-molecule compounds, the CitA crystal structure was solved to 2.1 Å by X-ray crystallography. The solved structure shows that CitA lacks an NADH binding site that would afford allosteric regulation, which is atypical of most citrate synthases. However, a pyruvate molecule is observed within the analogous domain, suggesting pyruvate may instead be the allosteric regulator for CitA. Further, the R149 and R153 residues forming the charged portion of the pyruvate binding pocket were mutated to glutamate and methionine, respectively, to assess the effect of mutations on activity. Protein thermal shift assay shows thermal stabilization of CitA in the presence of pyruvate compared to the two CitA variants designed to decrease pyruvate affinity. Solved crystal structures of both variants show no significant structural changes. However, the catalytic efficiency of the R153M variant increases by 2.6-fold. Additionally, we show that covalent modification of C143 of CitA by Ebselen completely arrests enzyme activity. Similar inhibition is observed using two spirocyclic Michael acceptor containing compounds, which inhibit CitA with IC app 50 values of 6.6 and 10.9 μM. A crystal structure of CitA modified by Ebselen was solved, but significant structural changes were lacking. Considering that covalent modification of C143 inactivates CitA and the proximity of C143 to the pyruvate binding site, this suggests that structural and/or chemical changes in this sub-domain are responsible for regulating CitA enzymatic activity.

60 APPLIED LIFE SCIENCES↗

Atmospheric measurements of pyruvic and formic acid

Pyruvic acid, a product of the atmospheric oxidation of cresols and probably of isoprene, has been determined together with formic acid in atmospheric aerosols and rain as well as in the vapor phase. Both acids are present predominantly as vapor; only about 10-20 percent of the total atmospheric pyruvate and 1-2 percent of the total formate are in the particulate phase. The concentrations of pyruvic and formic acid are highly correlated, with typical formic-to-pyruvic ratios of 10-30 in the gas phase, 20-30 in rain, and 2-10 in aerosols. The gas-phase and rain ratios are comparable to those predicted to result from isoprene oxidation. Pyruvic acid levels were similar in the eastern United States (during summer) and the Amazon Basin, suggesting that natural processes, particularly the photochemical oxidation of isoprene, could account for most of the pyruvic acid present in the atmosphere.

Andreae, Meinrat O.↗

Structural Basis for Flip-Flop Action of Thiamin Pyrophosphate-Dependent Enzymes Revealed by Human Pyruvate Dehydrogenase

Thiamin pyrophosphate (TPP), the biologically active form of vitamin BI, is a cofactor of enzymes catalyzing reactions involving the cleavage of a carbon-carbon bond adjacent to an oxo group. TPP-dependent enzymes show a common mechanism of TPP activation by: (1) forming the ionic N-H...O(sup -) hydrogen bonding between the N1' atom of the aminopirymidine ring of the coenzyme and intrinsic gamma-carboxylate group of glutamate and (2) imposing an "active" V-conformation that brings the N4' atom of the aminopirymidine to the distance required for the intramolecular C-H.. .N hydrogen bonding with the thiazolium C2 atom. Within these two hydrogen bonds that rapidly exchange protons, protonation of the N1' atom is strictly coordinated with the deprotonation of the 4' -amino group and eventually abstraction of the proton from C2. The human pyruvate dehydrogenase Elp, component of human pyruvate dehydrogenase complex, catalyzes the irreversible decarboxylation of the pyruvate followed by the reductive acetylation of the lipoyl group of dihydrolipoyl acyltransferase. Elp is alpha(sub 2)beta(sub2)-heterotetrameric with a molecular mass of I54 kDa, which has two catalytic sites, each providing TPP and magnesium ion as cofactors and each formed on the interface between the PP and PYR domains. The dynamic nonequivalence of two otherwise chemically equivalent catalytic sites has been observed and the flip-flop mechanism was suggested, according to which two active sites affect each other and in which different steps of the catalytic reaction are performed in each of the sites at any given moment. Based on specific futures of human pyruvate dehydrogenase including rigid and flexible connections between domains that bind the cofactor we propose a mechanistic model for the flip-flop action of this enzyme. We postulate that the dynamic protein environment drives the exchange of tautomers in the 4' -aminopyrimidine ring of the cofactor through a concerted shuttl-like motion of tightly connected domains. The dynamic exchange of those tautomers, in turns, is required during the reactions of pyruvate decarboxylation and reductive acetylation of lipoamide. Thus the shuttle-like motion of the domains is coordinated with the reactions of decarboxylation and acetylation, which are carried out in each of the cofactor sites resulting in a flip-flop action of the enzyme. The structure-derived mechanism of action of human pyruvate dehydrogenase may be likely common for other TPP-dependent enzymes.

Dominiak, Paulina↗

Structural Basis for Flip-Flop Action of Thiamin-Dependent Enzymes Revealed by Crystal Structure of Human Pyruvate Dehydrogenase

The biologically active derivative of vitamin B1; thiamin pyrophosphate; is used as cofactor by many enzymes that perform a wide range of catalytic functions in the pathways of energy production. In alpha2beta2-heterotetrameric human pyruvate dehydrogenase, the first catalytic component enzyme of human pyruvate dehydrogenase complex, this cofactor is used to cleave the C(sup alpha)-C(=0) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase, the second catalytic component of the complex. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites have puzzled researchers from earlier functional studies of this enzyme. In order to gain insight into the mechanism of action of this enzyme, we determined the crystal structure of the holoform of human pyruvate dehydrogenase at 1.958, resolution. We propose a kinetic model for the flip-flop action of this enzyme through the concerted approx. 2A, shuttle-like motion of the heterodimers. The similarity of thiamin pyrophosphate binding in human pyruvate dehydrogenase and other functionally related enzymes suggests this newly defined mechanism of shuttle-like motion of domains to be common for the family of thiamin pyrophosphate-dependent enzymes.

Ciszak, Ewa↗

The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation

Human liver pyruvate kinase (hlPYK) catalyzes the final step in glycolysis, the formation of pyruvate (PYR) and ATP from phosphoenolpyruvate (PEP) and ADP. Fructose 1,6-bisphosphate (FBP), a pathway intermediate of glycolysis, serves as an allosteric activator of hlPYK. Zymomonas mobilis pyruvate kinase (ZmPYK) performs the final step of the Entner-Doudoroff pathway, which is similar to glycolysis in that energy is harvested from glucose and pyruvate is generated. The Entner-Doudoroff pathway does not have FBP as a pathway intermediate, and ZmPYK is not allosterically activated. In this work, we solved the 2.4 Å X-ray crystallographic structure of ZmPYK. The protein is dimeric in solution as determined by gel filtration chromatography, but crystallizes as a tetramer. The buried surface area of the ZmPYK tetramerization interface is significantly smaller than that of hlPYK, and yet tetramerization using the standard interfaces from higher organisms provides an accessible low energy crystallization pathway. Interestingly, the ZmPYK structure showed a phosphate ion in the analogous location to the 6-phosphate binding site of FBP in hlPYK. Circular Dichroism (CD) was used to measure melting temperatures of hlPYK and ZmPYK in the absence and presence of substrates and effectors. The only significant difference was an additional phase of small amplitude for the ZmPYK melting curves. We conclude that the phosphate ion plays neither a structural or allosteric role in ZmPYK under the conditions tested. In conclusion, we hypothesize that ZmPYK does not have sufficient protein stability for activity to be tuned by allosteric effectors as described for rheostat positions in the allosteric homologues.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Facile hyperpolarization chemistry for molecular imaging and metabolic tracking of [1– 13 C]pyruvate in vivo

Hyperpolarization chemistry based on reversible exchange of parahydrogen, also known as Signal Amplification By Reversible Exchange (SABRE), is a particularly simple approach to attain high levels of nuclear spin hyperpolarization, which can enhance NMR and MRI signals by many orders of magnitude. SABRE has received significant attention in the scientific community since its inception because of its relative experimental simplicity and its broad applicability to a wide range of molecules, however, in vivo detection of molecular probes hyperpolarized by SABRE has remained elusive. Here we describe a first demonstration of SABRE-hyperpolarized contrast detected in vivo, specifically using hyperpolarized [1– 13 C]pyruvate. Biocompatible formulations of hyperpolarized [1– 13 C]pyruvate in, both, methanol-water, and ethanol-water mixtures followed by dilution with saline and catalyst filtration were prepared and injected into healthy Sprague Dawley and Wistar rats. Effective hyperpolarization-catalyst removal was performed with silica filters without major losses in hyperpolarization. Metabolic conversion of pyruvate to lactate, alanine, and bicarbonate was detected in vivo. Pyruvate-hydrate was also observed as a minor byproduct. Measurements were performed on the liver and kidney at 4.7 T via time-resolved spectroscopy and chemical-shift-resolved MRI. In addition, whole-body metabolic measurements were obtained using a cryogen-free 1.5 T MRI system, illustrating the utility of combining lower-cost MRI systems with simple, low-cost hyperpolarization chemistry to develop safe and scalable molecular imaging.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Spin dynamics of [1,2- 13 C 2 ]pyruvate hyperpolarization by parahydrogen in reversible exchange at micro Tesla fields

Hyperpolarization of 13 C-pyruvate via Signal Amplification By Reversible Exchange (SABRE) is an important recent discovery because of both the relative simplicity of hyperpolarization and the central biological relevance of pyruvate as a biomolecular probe for in vitro or in vivo studies. Here, we analyze the [1,2- 13 C 2 ]pyruvate-SABRE spin system and its field dependence theoretically and experimentally. We provide first-principles analysis of the governing 4-spin dihydride- 13 C 2 Hamiltonian and numerical spin dynamics simulations of the 7-spin dihydride- 13 C 2 –CH 3 system. Furthermore, the analytical and the numerical results are compared to matching systematic experiments. With these methods we unravel the observed spin state mixing of singlet states and triplet states at microTesla fields and we also analyze the dynamics during transfer from micro-Tesla field to high field for detection to understand the resulting spectra from the [1,2- 13 C 2 ]pyruvate-SABRE system.

13C pyruvate↗

Crystallization and initial X-ray diffraction analysis of human pyruvate dehydrogenase

Human pyruvate dehydrogenase (E1) is a component enzyme of the pyruvate dehydrogenase complex. The enzyme catalyzes the irreversible decarboxylation of pyruvic acid and the rate-limiting reductive acetylation of the lipoyl moiety linked to the dihydrolipoamide acetyltransferase component of the pyruvate dehydrogenase complex. E1 is an alpha(2)beta(2) tetramer ( approximately 154 kDa). Crystals of this recombinant enzyme have been grown in polyethylene glycol 3350 using a vapor-diffusion method at 295 K. The crystals are characterized as orthorhombic, space group P2(1)2(1)2(1), with unit-cell parameters a = 64.2, b = 126.9, c = 190.2 A. Crystals diffracted to a minimum d spacing of 2.5 A. The asymmetric unit contains one alpha(2)beta(2) tetrameric E1 assembly; self-rotation function analysis showed a pseudo-twofold symmetry relating the two alphabeta dimers.

Pyruvate Dehydrogenase Complex/chemistry↗

Glucose assimilation rate determines the partition of flux at pyruvate between lactic acid and ethanol in Saccharomyces cerevisiae

Engineered Saccharomyces cerevisiae expressing a lactic acid dehydrogenase can metab- olize pyruvate into lactic acid. However, three pyruvate decarboxylase (PDC) isozymes drive most carbon flux toward ethanol rather than lactic acid. Deletion of endoge- nous PDCs will eliminate ethanol production, but the resulting strain suffers from C 2 auxotrophy and struggles to complete a fermentation. Engineered yeast assimilating xylose or cellobiose produce lactic acid rather than ethanol as a major product with- out the deletion of any PDC genes. We report here that sugar flux, but not sensing, contributes to the partition of flux at the pyruvate branch point in S. cerevisiae express- ing the Rhizopus oryzae lactic acid dehydrogenase (LdhA). While the membrane glucose sensors Snf3 and Rgt2 did not play any direct role in the option of predominant product, the sugar assimilation rate was strongly correlated to the partition of flux at pyruvate: fast sugar assimilation favors ethanol production while slow sugar assimilation favors lactic acid. Applying this knowledge, we created an engineered yeast capable of simultaneously converting glucose and xylose into lactic acid, increasing lactic acid production to approximately 17 g L –1 from the 12 g L –1 observed during sequential consumption of sugars. This work elucidates the carbon source-dependent effects on product selection in engineered yeast.

59 BASIC BIOLOGICAL SCIENCES↗

Mutual-information based optimal experimental design for hyperpolarized $$^{13}$$C-pyruvate MRI

Abstract A key parameter of interest recovered from hyperpolarized (HP) MRI measurements is the apparent pyruvate-to-lactate exchange rate, $$k_{{\textrm PL}}$$ k P L , for measuring tumor metabolism. This manuscript presents an information-theory-based optimal experimental design approach that minimizes the uncertainty in the rate parameter, $$k_{{\textrm PL}}$$ k P L , recovered from HP-MRI measurements. Mutual information is employed to measure the information content of the HP measurements with respect to the first-order exchange kinetics of the pyruvate conversion to lactate. Flip angles of the pulse sequence acquisition are optimized with respect to the mutual information. A time-varying flip angle scheme leads to a higher parameter optimization that can further improve the quantitative value of mutual information over a constant flip angle scheme. However, the constant flip angle scheme, 35 and 28 degrees for pyruvate and lactate measurements, leads to an accuracy and precision comparable to the variable flip angle schemes obtained from our method. Combining the comparable performance and practical implementation, optimized pyruvate and lactate flip angles of 35 and 28 degrees, respectively, are recommended.

97 MATHEMATICS AND COMPUTING↗