Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves

We have examined the localization of the first two enzymes in the branched-chain amino acid (BCAA) catabolic pathway: the branched-chain aminotransferase (BCAT) isozymes (mitochondrial BCATm and cytosolic BCATc) and the branched-chain α-keto acid dehydrogenase (BCKD) enzyme complex. Antibodies specific for BCATm or BCATc were used to immunolocalize the respective isozymes in cryosections of rat tissues. BCATm was expressed in secretory epithelia throughout the digestive tract, with the most intense expression in the stomach. BCATm was also strongly expressed in secretory cells of the exocrine pancreas, uterus, and testis, as well as in the transporting epithelium of convoluted tubules in kidney. In muscle, BCATm was located in myofibrils. Liver, as predicted, was not immunoreactive for BCATm. Unexpectedly, BCATc was localized in elements of the autonomic innervation of the digestive tract, as well as in axons in the sciatic nerve. The distributions of BCATc and BCATm did not overlap. BCATm-expressing cells also expressed the second enzyme of the BCAA catabolic pathway, BCKD. In selected monkey and human tissues examined by immunoblot and/or immunohistochemistry, BCATm and BCATc were distributed in patterns very similar to those found in the rat. The results show that BCATm is in a position to regulate BCAA availability as protein precursors and anabolic signals in secretory portions of the digestive and other organ systems. The unique expression of BCATc in neurons of the peripheral nervous system, without coexpression of BCKD, raises new questions about the physiological function of this BCAT isozyme.

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Impaired branched chain amino acid metabolism alters feeding behavior and increases orexigenic neuropeptide expression in the hypothalamus

Journal of Endocrinology ◽

10.1530/joe-11-0270 ◽

2011 ◽

Vol 212 (1) ◽

pp. 85-94 ◽

Cited By ~ 14

Author(s):

Megan N Purpera ◽

Li Shen ◽

Marzieh Taghavi ◽

Heike Münzberg ◽

Roy J Martin ◽

...

Keyword(s):

Amino Acid ◽

Food Intake ◽

Feeding Behavior ◽

Control Diet ◽

Peripheral Tissues ◽

Protein Status ◽

Branched Chain Amino Acid ◽

Branched Chain ◽

Branched Chain Aminotransferase ◽

Deficient Mice

Elevation of dietary or brain leucine appears to suppress food intake via a mechanism involving mechanistic target of rapamycin, AMPK, and/or branched chain amino acid (BCAA) metabolism. Mice bearing a deletion of mitochondrial branched chain aminotransferase (BCATm), which is expressed in peripheral tissues (muscle) and brain glia, exhibit marked increases in circulating BCAAs. Here, we test whether this increase alters feeding behavior and brain neuropeptide expression. Circulating and brain levels of BCAAs were increased two- to four-fold in BCATm-deficient mice (KO). KO mice weighed less than controls (25.9 vs 20.4 g,P<0.01), but absolute food intake was relatively unchanged. In contrast to wild-type mice, KO mice preferred a low-BCAA diet to a control diet (P<0.05) but exhibited no change in preference for low- vs high-protein (HP) diets. KO mice also exhibited low leptin levels and increased hypothalamicNpyandAgrpmRNA. Normalization of circulating leptin levels had no effect on either food preference or the increasedNpyandAgrpmRNA expression. If BCAAs act as signals of protein status, one would expect reduced food intake, avoidance of dietary protein, and reduction in neuropeptide expression in BCATm-KO mice. Instead, these mice exhibit an increased expression of orexigenic neuropeptides and an avoidance of BCAAs but not HP. These data thus suggest that either BCAAs do not act as physiological signals of protein status or the loss of BCAA metabolism within brain glia impairs the detection of protein balance.

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Influence of Dietary Protein Levels and Hydrocortisone Administration on the Branched-chain Amino Acid Transaminase Activity in Rat Tissues

Journal of Nutrition ◽

10.1093/jn/95.3.493 ◽

1968 ◽

Vol 95 (3) ◽

pp. 493-497 ◽

Cited By ~ 44

Author(s):

Tsutomu Mimura ◽

Chisae Yamada ◽

Marian E. Swendseid

Keyword(s):

Amino Acid ◽

Dietary Protein ◽

Rat Tissues ◽

Transaminase Activity ◽

Protein Levels ◽

Branched Chain Amino Acid ◽

Hydrocortisone Administration ◽

Branched Chain

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Branched-chain amino acid metabolism and alanine formation in rat muscles in vitro. Mitochondrial-cytosolic interrelationships

Biochemical Journal ◽

10.1042/bj2250737 ◽

1985 ◽

Vol 225 (3) ◽

pp. 737-743 ◽

Cited By ~ 16

Author(s):

K Snell ◽

D A Duff

Keyword(s):

Amino Acid ◽

Aspartate Aminotransferase ◽

Alanine Aminotransferase ◽

Amino Acid Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Acid Metabolism ◽

Branched Chain Amino Acid ◽

Alanine Synthesis ◽

Branched Chain ◽

Branched Chain Aminotransferase

Muscle branched-chain amino acid metabolism is coupled to alanine formation via branched-chain amino acid aminotransferase and alanine aminotransferase, but the subcellular distributions of these and other associated enzymes are uncertain. Recovery of branched-chain aminotransferase in the cytosol fraction after differential centrifugation was shown to be accompanied by leakage of mitochondrial-matrix marker enzymes. By using a differential fractional extraction procedure, most of the branched-chain aminotransferase activity in rat muscle was located in the mitochondrial compartment, whereas alanine aminotransferase was predominantly in the cytosolic compartment. Phosphoenolpyruvate carboxykinase, like aspartate aminotransferase, was approximately equally distributed between these subcellular compartments. This arrangement necessitates a transfer of branched-chain amino nitrogen and carbon from the mitochondria to the cytosol for alanine synthesis de novo to occur. In incubations of hemidiaphragms from 48 h-starved rats with 3mM-valine or 3mM-glutamate, the stimulation of alanine release was inhibited by 69% by 1 mM-aminomethoxybut-3-enoate, a selective inhibitor of aspartate aminotransferase. Leucine-stimulated alanine release was unaffected. These data implicate aspartate aminotransferase in the transfer of amino acid carbon and nitrogen from the mitochondria to the cytosol, and suggest that oxaloacetate, via phosphoenolpyruvate carboxykinase, can serve as an intermediate on the route of pyruvate formation for muscle alanine synthesis.

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Effect of Branched-Chain Keto-acids and Dietary Protein Content on the Activity of Branched-Chain Amino Acid Transferase in Rat Tissues

Journal of Nutrition ◽

10.1093/jn/108.1.40 ◽

1978 ◽

Vol 108 (1) ◽

pp. 40-45 ◽

Cited By ~ 11

Author(s):

Winnie Chan ◽

Mackenzie Walser

Keyword(s):

Amino Acid ◽

Protein Content ◽

Dietary Protein ◽

Rat Tissues ◽

Branched Chain Amino Acid ◽

Keto Acids ◽

Branched Chain ◽

Branched Chain Keto Acids

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A pathogen branched-chain amino acid catabolic pathway subverts host survival by impairing energy metabolism and the mitochondrial UPR

PLoS Pathogens ◽

10.1371/journal.ppat.1008918 ◽

2020 ◽

Vol 16 (9) ◽

pp. e1008918

Author(s):

Siraje Arif Mahmud ◽

Mohammed Adnan Qureshi ◽

Madhab Sapkota ◽

Mark W. Pellegrino

Keyword(s):

Amino Acid ◽

Energy Metabolism ◽

Catabolic Pathway ◽

Branched Chain Amino Acid ◽

Branched Chain

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Effects of liver failure on the enzymes in the branched-chain amino acid catabolic pathway

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2003.07.022 ◽

2004 ◽

Vol 313 (2) ◽

pp. 381-385 ◽

Cited By ~ 16

Author(s):

Yoshiharu Shimomura ◽

Takashi Honda ◽

Hidemi Goto ◽

Toshiaki Nonami ◽

Tsuyoshi Kurokawa ◽

...

Keyword(s):

Amino Acid ◽

Liver Failure ◽

Catabolic Pathway ◽

Branched Chain Amino Acid ◽

Branched Chain

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Cytosolic and mitochondrial isoenzymes of branched-chain amino acid aminotransferase during development of the rat

Biochemical Journal ◽

10.1042/bj2020777 ◽

1982 ◽

Vol 202 (3) ◽

pp. 777-783 ◽

Cited By ~ 23

Author(s):

H Kadowaki ◽

W E Knox

Keyword(s):

Amino Acid ◽

Parenchymal Cell ◽

Adult Brain ◽

Rat Tissues ◽

Type I ◽

Liver Parenchymal Cell ◽

Unique Type ◽

Haematopoietic Cells ◽

Branched Chain Amino Acid ◽

Branched Chain

The isoenzymic forms of branched-chain amino acid aminotransferase in mitochondria of rat tissues were compared with the better-known cytosolic forms in order to find any regular pattern of expression of these isoenzymes during development. Mitochondria of all tissues examined except brain contained only a type-I isoenzyme differing from the cytosolic type-I isoenzyme in heat stability and activation by mercaptoethanol. Foetal and adult brain mitochondria contained isoenzymes type III as well as type I. The large excess of type-I isoenzyme in foetal liver was localized in mitochondria, apparently of haematopoietic cells. The activity of this isoenzyme declined precipitously (by 80%) from day 19 of gestation at the same period and rate as does the volume fraction of haematopoietic cells that are then leaving the liver. Cortisol treatment accelerated the loss of these cells, and proportionally accelerated loss of the mitochondrial isoenzyme I. A development succession of type-I isoenzyme by the unique type II of liver parenchymal cell cytosols could not be demonstrated, since small, about equal, amounts of types I and II were always present in cytosols of foetal and adult liver. Developmental succession of isoenzymes within tissues was limited to cytosols and was demonstrated by the presence of cytosolic isoenzyme III in foetal and newborn skeletal muscle and kidney, organs which contain only isoenzyme I in the adult.

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