Enzyme Activities of NADPH-Forming Metabolic Pathways in Normal and Leukemic Leukocytes

Abstract With respect to the enzymes of NADPH-forming metabolic pathways in human leukocytes: (a) Glucose-6phosphate dehydrogenase and phosphogluconate dehydrogenase (decarboxylating) were less active in leukocytes (mostly myeloblasts) from eight patients with acute myeloblastic leukemia (I) than in leukocytes (mostly granulocytes) from 16 normal subjects (II) or 16 patients with chronic myelocytic leukemia (III). (b) Of the enzymes of the citrate cleavage pathway, ATP citrate lyase and malate dehydrogenase (decarboxylating) (NADP+) were virtually absent in the cells studied. (c) Isocitrate dehydrogenase (NADP+), aspartate aminotransferase, and alanine aminotransferase, which, together with the much more active malate dehydrogenase, constitute a newly proposed NADPH-forming metabolic cycle, showed a higher activity in I than in II or III, and therefore could compensate, as concerns NADPHgeneration, for the low activity of pentose cycle dehydrogenases. We are not sure whether the enzymatic characteristic of I cells is attributable to their immaturity or to their leukemic nature.

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Changes in activity of some enzymes involved in glucose utilization and formation in developing rat liver

Biochemical Journal ◽

10.1042/bj1060321 ◽

1968 ◽

Vol 106 (2) ◽

pp. 321-329 ◽

Cited By ~ 78

Author(s):

R. G. Vernon ◽

D G Walker

Keyword(s):

Malate Dehydrogenase ◽

Rat Liver ◽

Postnatal Period ◽

Supernatant Fraction ◽

Atp Citrate Lyase ◽

Carboxylase Activity ◽

Phosphogluconate Dehydrogenase ◽

Citrate Lyase ◽

Glucose 6 Phosphate Dehydrogenase ◽

Developing Rat

1. The activities of some enzymes involved in both the utilization of glucose (pyruvate kinase, ATP citrate lyase, NADP-specific malate dehydrogenase, glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and NADP-specific isocitrate dehydrogenase, all present in the supernatant fraction of liver homogenates) and the formation of glucose by gluconeogenesis (glucose 6-phosphatase in the whole homogenate and fructose 1,6-diphosphatase, phosphopyruvate carboxylase, NAD-specific malate dehydrogenase and fumarase in the supernatant fraction) have been determined in rat liver around birth and in the postnatal period until the end of weaning. 2. The activities of those enzymes involved in the conversion of glucose into lipid are low during the neonatal period and increase with weaning. NADP-specific malate dehydrogenase first appears and develops at the beginning of the weaning period. 3. The marked increase in cytoplasmic phosphopyruvate carboxylase activity at birth is probably the major factor initiating gluconeogenesis at that time. 4. The results are discussed against the known changes in dietary supplies and the known metabolic patterns during the period of development.

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Genetic control of metabolism: enzyme studies of the obese and adipose mutants in the mouse

Genetics Research ◽

10.1017/s0016672300013586 ◽

1972 ◽

Vol 20 (1) ◽

pp. 51-64 ◽

Cited By ~ 23

Author(s):

Grahame Bulfield

Keyword(s):

Enzyme Activity ◽

Malate Dehydrogenase ◽

Primary Lesion ◽

Gas Liquid Chromatography ◽

Wild Type ◽

Atp Citrate Lyase ◽

Citrate Lyase ◽

Lyase Activity ◽

Metabolism Enzyme ◽

Pheno Type

SUMMARYThe activity of several enzymes has been determined in the livers of homozygous obese and adipose mice, their normal litter-mates, and phenocopies induced in normal mice by aurothioglucose (ATG) injections.Obese, adipose and ATG mice had higher activities of ATP citrate lyase, malic enzyme (NADP malate dehydrogenase) and pyruvate kinase than normal mice. Heterozygote activities are indistinguishable from wild-type. There was no difference between normal and fat litter-mates in the activity of malate dehydrogenase (NAD-linked), lactate dehydrogenase, isocitrate dehydrogenase and fumarase.Crosses between mice doubly heterozygous for roth the ad and ob genes produced offspring that were only ‘fat’ or ‘normal’ and no offspring could be phenotypically recognized as the double mutant, either physically or in terms of ATP citrate lyase activity.Gas–liquid chromatography of the fatty acids of the depot fat showed no differences between any of the types of litter-mate.The alterations found in enzyme activity in obese and adipose mice are compared to several other enzyme activity differences reported in the literature for obese mice. These are discussed in relation to genetical criteria that may be estarlished to assess, from quantitative data, whether an enzyme is the site of the primary lesion in a mutant pheno-type. Some general observations are made on genetics and the control of metabolism.

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Variations in the activity of several enzymes in the mammary glands of non-pregnant, pregnant and lactating rabbits

Biochemical Journal ◽

10.1042/bj1160657 ◽

1970 ◽

Vol 116 (4) ◽

pp. 657-661 ◽

Cited By ~ 8

Author(s):

P. E. Hartmann ◽

E. A. Jones

Keyword(s):

Mammary Gland ◽

Small Mammals ◽

Enzyme Activities ◽

Mammary Glands ◽

Acetyl Coa Carboxylase ◽

Atp Citrate Lyase ◽

Acetyl Coa ◽

Phosphogluconate Dehydrogenase ◽

Citrate Lyase ◽

Lactation Cycle

1. The enzymes phosphofructokinase (EC 2.7.1.11), 6-phosphogluconate dehydrogenase (EC 1.1.1.44), phosphoglucomutase (EC 2.7.5.1), ATP–citrate lyase (EC 4.1.3.8), acetyl-CoA carboxylase (EC 6.4.1.2) and acetyl-CoA synthetase (EC 6.2.1.1) were assayed in rabbit mammary glands at various stages of the pregnancy–lactation cycle. 2. The activities of all enzymes were low during pregnancy and, with the exception of phosphofructokinase, in non-pregnant animals. Two- to ten-fold increases in enzyme activities occurred over the first 20 days of lactation. Although milk yield was considerably decreased, the enzyme activities remained elevated in late lactation (45 days after parturition). 3. These findings are discussed in relation to mammary-gland metabolism and compared with similar observations previously made on ruminants and other small mammals.

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Acetyl-CoA synthetase, NADP malate dehydrogenase and ATP citrate lyase in the degenerating peripheral nerve

Brain Research ◽

10.1016/0006-8993(68)90127-3 ◽

1968 ◽

Vol 10 (2) ◽

pp. 245-251 ◽

Cited By ~ 1

Author(s):

Vincenzo Bonavita ◽

Federico Piccoli ◽

Salvatore Serra

Keyword(s):

Peripheral Nerve ◽

Malate Dehydrogenase ◽

Atp Citrate Lyase ◽

Acetyl Coa ◽

Citrate Lyase

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Response of lipogenic enzymes to overfeeding in liver and adipose tissue of light and heavy breeds of chicks

British Journal Of Nutrition ◽

10.1079/bjn19780021 ◽

1978 ◽

Vol 39 (1) ◽

pp. 151-157 ◽

Cited By ~ 24

Author(s):

Niva Shapira ◽

I. Nir ◽

P. Budowski

Keyword(s):

Adipose Tissue ◽

Fatty Acid Synthetase ◽

Fat Content ◽

Acetyl Coa Carboxylase ◽

Lipogenic Enzymes ◽

Atp Citrate Lyase ◽

Phosphogluconate Dehydrogenase ◽

Citrate Lyase ◽

Generating Capacity ◽

Glucose 6 Phosphate Dehydrogenase

1. Chicks, 3-d-old, of a heavy breed (HB) and a light breed (LB) were overfed for 18 d. The activities of acetyl-CoA carboxylase (EC 6.4.1.2; CBX), fatty acid synthetase (FAS), ATP citrate lyase (EC 4.1.3.8; CCE), NADP-malate dehydrogenase (decarboxylating) (EC 1.1.1.40; ME), 6-glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G6PDH) and phosphogluconate dehydrogenase (EC 1.1.1.44; 6PGDH) were determined in abdominal adipose tissue (AT) and liver samples of overfed and ad lib.-fed chicks. Size and fat content of liver and adipose tissue were also determined in order to evaluate the extent of obesity.2. On ad lib.-feeding HB chicks consumed more food, gained more weight and deposited more fat than the corresponding LB chicks. Their lipogenic enzymes were more active than in the LB chicks in both adipose tissue and liver. The increase in food consumption (%) that could be achieved by overfeeding was three times greater in the LB chicks than in the HB chicks.3. Overfeeding increased the weight and fat content of liver and AT in both breeds. The specific activities of CBX, FAS, CCE and ME in liver and AT increased in the LB chicks only and the total activities of liver and AT enzymes increased much more in the LB chicks than in the HB chicks in which the increase was derived mainly from tissue enlargement.4. The activity of the pentose cycle dehydrogenases was very low in liver, but in AT about one third of the NADPH generating capacity could be accounted for by these dehydrogenases.5. The results show that lipogenic enzymes of chicks respond to an increased substrate flux. It is suggested that the enlarged liver, the higher participation of AT in lipogenesis and the uninterrupted supply of cropstored excess food enable the chick to accommodate the increased amounts of substrate with only moderate enzymic adaptation.

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The metabolic fate of the products of citrate cleavage. Adenosine triphosphate citrate lyase and nicotinamide–adenine dinucleotide phosphate-linked malate dehydrogenase in foetal and adult liver from ruminants and non-ruminants

Biochemical Journal ◽

10.1042/bj1080705 ◽

1968 ◽

Vol 108 (5) ◽

pp. 705-713 ◽

Cited By ~ 22

Author(s):

R. W. Hanson ◽

F. J. Ballard

Keyword(s):

Fatty Acids ◽

Malate Dehydrogenase ◽

Rat Liver ◽

Phosphoenolpyruvate Carboxykinase ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Atp Citrate Lyase ◽

Adult Rat ◽

Liver Slices ◽

Citrate Lyase ◽

Foetal Rat

1. Foetal rat liver slices incorporate the C-3 of aspartate and C-2 of glutamate into fatty acids at rates equal to those observed with adult rat liver slices. Incorporation of either of these labelled carbon atoms into fatty acids would require a functioning citrate-cleavage pathway which consists of the enzymes ATP–citrate lyase, NAD–malate dehydrogenase and NADP–malate dehydrogenase. However, NADP–malate dehydrogenase is present in foetal rat liver at only 5% of the activity detectable in adult rat liver. 2. From these findings and the effect of cofactors on the formation of 14CO2 from [1,5−14C2]citrate in liver supernatant fractions (100000g), it is suggested that NADP–malate dehydrogenase limits the citrate-cleavage sequence. 3. Measurement of the citrate-cleavage pathway by incorporation studies with [3−14C]aspartate and [U−14C]glucose and by determining the activities of ATP–citrate lyase and NADP–malate dehydrogenase have shown that this sequence of reactions is present in the liver of the bovine foetus but not in the adult. However, C-2 of glutamate is not incorporated into fatty acids or non-saponifiable lipid by bovine liver slices. This finding as well as those presented above for the adult and foetal rat liver are interpreted on the basis of a competition between phosphoenolpyruvate carboxykinase and NAD–malate dehydrogenase for oxaloacetate produced by the cleavage of citrate in the cytosol.

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The effects of pregnancy, lactation and involution on the metabolism of glucose and acetate by rat liver tissue

Journal of Dairy Research ◽

10.1017/s0022029900014710 ◽

1973 ◽

Vol 40 (3) ◽

pp. 339-351 ◽

Cited By ~ 12

Author(s):

R. W. Smith

Keyword(s):

Fatty Acids ◽

Rat Liver ◽

Milk Fat ◽

Late Pregnancy ◽

Acetyl Coa Carboxylase ◽

Atp Citrate Lyase ◽

Phosphogluconate Dehydrogenase ◽

Citrate Lyase ◽

Pregnancy And Lactation ◽

Glucose 6 Phosphate Dehydrogenase

SummaryThe incorporation of 14C from [1-14C] and [6-14C]glucose and [2-14C]acetate into CO2 and fatty acids by rat liver slices was measured at intervals during pregnancy, lactation and involution.During late pregnancy, the rates of oxidation of the C-1 and C-6 atoms of glucose were respectively 65 and 40 % higher than those for unmated animals. These increases were maintained during lactation, but the highest values were observed 3 days after weaning. Pregnancy and lactation had little effect on the oxidation of [2-14C]acetate.The incorporation of14C from all 3 labelled substrates into fatty acids was increased by a factor of 3–4 during late pregnancy. There were further increases during lactation, and 3 days after weaning the values were as much as 10 times as high as those for unmated animals.The incorporation of both [14C]glucose and [14C]acetate into cholesterol was increased by a factor of 6–7 during lactation.The activities of the enzymes glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, ATP citrate lyase and acetyl-CoA carboxylase were also increased during lactation and involution.The similarity between the changes summarized above and those brought about by changes in the pattern of food intake is discussed, and the idea that fatty acids synthesized from non-lipid precursors in the liver may make some contribution to the formation of milk fat is also considered.

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New Therapies for Primary Hyperlipidaemia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab876 ◽

2021 ◽

Author(s):

Carlos A Aguilar-Salinas ◽

Rita A Gómez-Díaz ◽

Pablo Corral

Keyword(s):

Metabolic Pathways ◽

Real Life ◽

Lipid Lowering ◽

The Novel ◽

Recurrent Pancreatitis ◽

Atp Citrate Lyase ◽

Citrate Lyase ◽

Family Aggregation ◽

Primary Hyperlipidemia ◽

Primary Hyperlipidaemia

Abstract Primary hyperlipidemias include a heterogeneous set of monogenic and polygenic conditions characterized by a strong family aggregation, severe forms of hypercholesterolemia and/or hypertriglyceridemia, appearance early on life and a high risk of cardiovascular events and/or recurrent pancreatitis. In real life, a small proportion of the primary hyperlipidemia cases is recognized and treated properly. Our goal is to present an update of current and upcoming therapies for patients with primary hyperlipidemia. Recently, new lipid lowering medications have obtained FDA and/or EMA authorization. These drugs target metabolic pathways, including (ATP)-citrate lyase (bempedoic acid), PCSK9 (inclisiran), apo CIII (volanesorsen) and ANGPTL3 (volanesorsen), that have additive effects with the actions of the currently available therapies (i.e. statins, ezetimibe or fibrates). We discuss the potential clinical indications for the novel medications. To conclude, the addition of these new medications to the therapeutic options for primary hyperlipidemia patients may increase the likelihood to achieve the treatment targets. Also, it could be a safer alternative for subjects with side effects for the currently available drugs.

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Utilization and preferred metabolic pathway of ketone bodies for lipid synthesis by isolated rat hepatoma cells

AJP Cell Physiology ◽

10.1152/ajpcell.1995.269.1.c22 ◽

1995 ◽

Vol 269 (1) ◽

pp. C22-C27 ◽

Cited By ~ 22

Author(s):

L. A. Hildebrandt ◽

T. Spennetta ◽

C. Elson ◽

E. Shrago

Keyword(s):

Metabolic Pathway ◽

Metabolic Pathways ◽

Ketone Bodies ◽

Malignant Tumors ◽

Lipid Synthesis ◽

Hepatoma Cells ◽

Atp Citrate Lyase ◽

Citrate Lyase ◽

Morris Hepatoma ◽

Distribution Studies

Morris hepatoma 7777 cells freshly isolated from highly malignant tumors grown in the hindlimb of buffalo rats actively convert ketone bodies to cholesterol and fatty acids. On the basis of results obtained with (-)-hydroxycitrate, an inhibitor of the ATP citrate lyase enzyme, the metabolic pathway for acetoacetate conversion to lipids is exclusively cytoplasmic, whereas that for 3-hydroxybutyrate involves both extra- and intramitochondrial compartments. Subcellular distribution studies indicated accumulation and compartmentation of 3-hydroxybutyryl CoA primarily in the cytoplasm of hepatoma cells incubated with either ketone body. In contrast, the compartmentation of acetoacetyl CoA is dependent on whether the substrate is acetoacetate or 3-hydroxybutyrate. With acetoacetate, the acetoacetyl CoA is entirely cytoplasmic, whereas with 3-hydroxybutyrate, it is equally divided between the intra- and extramitochondrial compartments. The results are discussed in terms of the known and proposed metabolic pathways for lipid synthesis from ketone bodies, particularly that from 3-hydroxybutyrate.

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