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Fatty acid synthesis and degradation are regulated largely by cellular energy dependence. Fatty acids serve
as long-term energy storage molecules. During starvation where ATP production from the breakdown of
glycogen cannot produce adequate amounts of energy, fatty acid degradation accelerates. On the other hand,
[23]
if there are adequate supplies of ATP and glycogen storage is full, then fatty acid synthesis can occur .
Amino acid synthesis and degradation
Amino acids and proteins remain a central aspect of cellular metabolism. While there have been over 300
amino acids described, only 20 are commonly found in mammalian proteins. Not surprisingly, these 20
[30]
amino acids are the only amino acids coded for by DNA . Of these, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, threonine, tryptophan, and valine are termed essential as they cannot be
synthesized by humans. Amino acids serve various roles in metabolism. In addition to protein synthesis,
they can be used for energy production and synthesis of hormones. In extreme situations where energy is
[22]
scarce and fatty acid reserves have been exhausted, protein turnover becomes a main source of energy .
Oxidation of proteins typically occurs in small quantities since the ammonia/ammonium byproduct is toxic
and must be transported bound to L-glutamine. L-glutamine can leave the tissue and be transported to the
liver for energy production with NH4+ excreted as urea. Alternatively, proteins can be metabolized by the
glucose-alanine cycle. When breakdown of muscle protein yields L-glutamate, a reaction with pyruvate
occurs yielding alanine and a-ketoglutarate. Alanine is then transported to the liver where transamination
occurs resulting in glutamate which subsequently undergoes deamination releasing NH4+ into the
urea cycle. Pyruvate is also a byproduct of the transamination reaction and can be used in the liver for
gluconeogenesis.

Integration of metabolic processes
Cellular metabolism is intertwined and tightly regulated. Glycolysis and the TCA cycle produce many
byproducts that may enter the ETC for oxidative phosphorylation or can be used for other purposes.
For example, the oxidation of glyceraldehyde 3-phosphate which occurs in glycolysis also results in the
production of NADH and H+. These molecules can serve as electron donors for the ETC. Similarly, FADH2
which is a byproduct of the reaction that converts succinate to fumarate in the TCA cycle can also serve as
an electron donor in the ETC.

Anaerobic and aerobic respiration are closely linked by the use of NAD+ and NADH. Production of lactate
during anerobic respiration is one of the main ways in which NADH and H+ are oxidized back into NAD+
which allows for the TCA cycle to continue without any significant changes. Ultimately, glycolysis, the TCA
cycle, gluconeogenesis, fatty acid metabolism, and protein synthesis are all interconnected and exist in a
highly regulated and interdependent environment designed to maintain homeostasis [31-33] .

ALTERATIONS IN METABOLISM OF MULTIPLE MYELOMA
Multiple changes in metabolism occur in myeloma cells which are summarized below and in Figure 1.
Understanding the metabolic alterations in MM has important implications in the care of patients with
MM. It sheds new light into our understanding of MM development and progression, and allows for
the assessment of predictive or prognostic biomarkers for optimal management of myeloma patients.
Importantly, it provides potentially novel therapeutic targets for the treatment of MM.

1
Over the last decade, several technologies such as mass spectrometry, H-nuclear magnetic resonance
(H-NMR) spectroscopy and mass spectrometry, and C stable isotope resolved metabolomics (SIRM) have
13
1
been used to determine metabolic alterations in monoclonal gammopathy of undetermined significance
(MGUS) patients, newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) and to compare
[34]
metabolic changes in drug resistant MM cells. Steiner et al. used mass spectrometry to analyze 188