Pyrroline-5-carboxylate reductase in human erythrocytes.

Yeh, Grace Chao; Harris, Shirley; Phang, James M.

doi:10.1172/jci110115

Cited by 38 publications

(18 citation statements)

References 13 publications

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“…2,19,20 P5CR has been shown to play a role in the regulation of de novo purine biosynthesis through the generation of NADP + , which is required for the synthesis of the purine precursor ribose 5-phosphate. 21 In human erythrocytes, the level of P5CR activity is comparable with the activity levels of major erythrocyte enzymes. This is consistent with the interpretation that the function of the enzyme in human erythrocytes may be to generate an oxidizing potential in the form of NADP + .…”

Section: Introductionmentioning

confidence: 92%

“…This is consistent with the interpretation that the function of the enzyme in human erythrocytes may be to generate an oxidizing potential in the form of NADP + . 21 In some mammalian cells, the inter-conversion of proline and P5C provides a metabolic shuttle of redox equivalents between the cytosol and mitochondria. P5C can be transported into cells as a source of oxidizing potential where its reduction to proline generates NADP + .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Crystal Structures of Δ1-Pyrroline-5-carboxylate Reductase from Human Pathogens Neisseria meningitides and Streptococcus pyogenes

Nocek¹,

Chang²,

Li³

et al. 2005

Journal of Molecular Biology

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L-Proline is an amino acid that plays an important role in proteins uniquely contributing to protein folding, structure, and stability, and this amino acid serves as a sequence-recognition motif. Proline biosynthesis can occur via two pathways, one from glutamate and the other from arginine. In both pathways, the last step of biosynthesis, the conversion of Δ 1 -pyrroline-5-carboxylate (P5C) to Lproline, is catalyzed by Δ 1 -pyrroline-5-carboxylate reductase (P5CR) using NAD(P)H as a cofactor. We have determined the first crystal structure of P5CR from two human pathogens, Neisseria meningitides and Streptococcus pyogenes, at 2.0Å and 2.15Å resolution, respectively. The catalytic unit of P5CR is a dimer composed of two domains, but the biological unit seems to be speciesspecific. The N-terminal domain of P5CR is an α/β/α sandwich, a Rossmann fold. The C-terminal dimerization domain is rich in α-helices and shows domain swapping. Comparison of the native structure of P5CR to structures complexed with L-proline and NADP + in two quite different primary sequence backgrounds provides unique information about key functional features: the active site and the catalytic mechanism. The inhibitory L-proline has been observed in the crystal structure.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Δ1-Pyrroline-5-carboxylate Reductase from Human Pathogens Neisseria meningitides and Streptococcus pyogenes

Nocek¹,

Chang²,

Li³

et al. 2005

Journal of Molecular Biology

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“…NADP+ severely diminishes erythrocyte P5CR activity, but NAD+ does not. Furthermore, erythrocyte P5CR activity is not significantly affected by proline (10). These observations suggest that NADP+ is the physiologically important end product of this reaction in erythrocytes.…”

mentioning

confidence: 66%

“…On the other hand, the properties of fibroblast P5CR (10), particularly the decrease in its activity when proline is present and the absence of any effect of NADP', are more consistent with a role for this enzyme in the production of proline for incorporation into cell material, primarily collagen, a proline/hydroxyproline-rich protein.…”

mentioning

confidence: 70%

Proline metabolism in N2-fixing root nodules: energy transfer and regulation of purine synthesis.

Kohl

Schubert

Carter

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

132

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N2-fixing root nodules of soybean (Glycine max L. Merr.) convert atmospheric N2 to ammonia(um) in an energy-intensive enzymatic reaction. These nodules synthesize large quantities of purines because nitrogen fixed by bacteria contained within this tissue is transferred to the shoots in the form of ureides, which are degradation products of purines. In animal systems, it has been proposed that proline biosynthesis by pyrroline-5-carboxylate reductase (P5CR) is used to generate the NADP+ required for the synthesis of the purine precursor ribose 5-phosphate. We have examined the levels, properties, and location of P5CR and proline dehydrogenase (ProDH) in soybean nodules. Nodule P5CR was found in the plant cytosol. Its activity was substantially higher than that reported for other animal and plant tissues and is 4-fold higher than in pea (Pisum sativum) nodules (which export amides).The Km for NADPH was lower by a factor of 25 than the Km for NADH, while the Vm. with NADPH was one-third of that with NADH. P5CR activity was diminished by NADP+ but not by proline. These characteristics are consistent with a role for P5CR in supporting nodule purine biosynthesis rather than in producing proline for incorporation into protein. ProDH activity was divided between the bacteroids and plant cytosol, but <2% was in the mitochondria-rich fractions. The specific activity of ProDH in soybean nodule bacteroids was comparable to that in rat liver mitochondria. In addition, we propose that some of the proline synthesized in the plant cytosol by P5CR is catabolized within the bacteroids by ProDH and that this represents a novel mechanism for transferring energy from the plant to its endosymbiont. N2 fixation in legumes is a symbiotic process in which bacteria of the genus Bradyrhizobium or Rhizobium infect root cells and form specialized organs (nodules) within which N2 is reduced to NH'. Fixation of N2 is an energyintensive process, requiring a total of 25-30 ATP per N atom fixed. Of this total, 12-14 ATP per N are required within the bacteroid to reduce N2. As much as 10-30% of the total photosynthetic capacity of the plant is used to support this process (1). The energy-yielding metabolite(s) supplied by the host to the bacteroid, the symbiotic form of the bacterium, is not known. However, one attractive suggestion is that bacteroids import and oxidize a nitrogenous compound, such as glutamate (2). The nitrogen fixed in the bacteroid is exported as ammonia(um) to the infected host cell, where it is packaged for export to the rest of the plant. Legumes of temperate origin (e.g., peas) export nitrogen as amides (principally asparagine), whereas legumes of tropical origin (e.g., soybeans) export the ureides, allantoin, and allantoic acid. Ureide biogenesis proceeds by way of synthesis of purine ribonucleotides (3). This pathway is the same as that found in microorganisms, fungi, and animals. The purines so formed are then oxidatively degraded to ureides (3). The estimated peak rate of de novo purine biosynthesis necessary t...

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“…The authors concluded that the same enzyme(s) catalyze(s) the reduction of both compounds, but are unable to catalyze the reduction of Δ 1 -pyrroline-5-carboxylate (Pyr5C) and P6C, which are isomers of P2C and Pyr2C, differing only in the position of the imine double bond. Pyr5C reductases that exist in various isoforms in mitochondria as well as in the cytosol were later characterized and shown to catalyze the reduction of both Pyr5C and P6C (Valle et al 1973; Yeh et al 1981). Note that enzymes that reduce Pyr5C/P6C and P2C/Pyr2C may be regarded as aldimine reductases and ketimine reductases (KRs), respectively.…”

Section: The Discovery Of Specific Cytosolic P2c Reductasesmentioning

confidence: 99%

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

2013

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The lysine catabolism pathway differs in adult mammalian brain from that in extracerebral tissues. The saccharopine pathway is the predominant lysine degradative pathway in extracerebral tissues, whereas the pipecolate pathway predominates in adult brain. The two pathways converge at the level of Δ1-piperideine-6-carboxylate (P6C), which is in equilibrium with its open-chain aldehyde form, namely, α-aminoadipate δ-semialdehyde (AAS). A unique feature of the pipecolate pathway is the formation of the cyclic ketimine intermediate Δ1-piperideine-2-carboxylate (P2C) and its reduced metabolite l-pipecolate. A cerebral ketimine reductase (KR) has recently been identified that catalyzes the reduction of P2C to l-pipecolate. The discovery that this KR, which is capable of reducing not only P2C but also other cyclic imines, is identical to a previously well-described thyroid hormone-binding protein [μ-crystallin (CRYM)], may hold the key to understanding the biological relevance of the pipecolate pathway and its importance in the brain. The finding that the KR activity of CRYM is strongly inhibited by the thyroid hormone 3,5,3′-triiodothyronine (T3) has far-reaching biomedical and clinical implications. The interrelationship between tryptophan and lysine catabolic pathways is discussed in the context of shared degradative enzymes and also potential regulation by thyroid hormones. This review traces the discoveries of enzymes involved in lysine metabolism in mammalian brain. However, there still remain unanswered questions as regards the importance of the pipecolate pathway in normal or diseased brain, including the nature of the first step in the pathway and the relationship of the pipecolate pathway to the tryptophan degradation pathway.

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Pyrroline-5-carboxylate reductase in human erythrocytes.

Cited by 38 publications

References 13 publications

Crystal Structures of Δ1-Pyrroline-5-carboxylate Reductase from Human Pathogens Neisseria meningitides and Streptococcus pyogenes

Crystal Structures of Δ1-Pyrroline-5-carboxylate Reductase from Human Pathogens Neisseria meningitides and Streptococcus pyogenes

Proline metabolism in N2-fixing root nodules: energy transfer and regulation of purine synthesis.

Lysine metabolism in mammalian brain: an update on the importance of recent discoveries

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